Nephron最新文献

Despite major advancements in transplant rejection physiopathology and the refinement of immunosuppressive therapies over the past decades, improvements in graft and patient survival remains limited. A potential explanation is the insufficient implementation of biomarkers for individualized alloimmune risk stratification in clinical transplantation. Enormous efforts have focused in the last decades on developing sensitive and specific biomarkers to enable more personalized, non-invasive rejection diagnostics and informed treatment decisions in the transplant process. These biomarkers have distinct purposes; pre-transplantation, biomarkers aim to improve current donor-recipient immunological matching and rule out preformed anti-donor immune memory, whereas post-transplantation, their main aim focuses on identifying anti-donor alloimmune activation and on-going subclinical rejection in a non-invasive manner. This review summarizes the most advanced biomarkers and immune assays in the field, categorizing them by their diagnostic, prognostic, and predictive capabilities, and discusses their current validation status and integration into clinical trial designs aimed at improving transplant outcomes. Among them, we here highlight those assessing alloimmune susceptibility or activation, such as donor/recipient HLA molecular matching, donor (HLA/non-HLA)-specific antibodies (DSA), donor-reactive memory T and B cells, peripheral gene expression profiling (GEP) as well as some specific circulating immune cell phenotypes; and furthermore, we discuss those biomarkers diagnosing on-going subclinical graft injury, including donor-derived cell-free DNA (dd-cfDNA), and urinary chemokines or transcriptional biomarkers. Most importantly, these biomarkers are often complementary: some reflect ongoing alloimmune responses and may guide immunosuppression decisions, while others may provide early warnings of allograft injury prior to clinical manifestation. While some have progressed to advanced validation stages with strong diagnostic and prognostic value, others remain in early development. Rigorous interventional clinical trials are warranted to establish their clinical utility and define their role in transplant precision medicine to ultimately improve current clinical outcomes.

Introduction: Ezrin is a protein that links the actin cytoskeleton to membrane proteins. The sodium chloride cotransporter (NCC) plays a key role in regulating total body electrolyte homeostasis and systemic blood pressure. Dapagliflozin, an SGLT2 inhibitor, is used to manage type 2 diabetes mellitus. We hypothesize dapagliflozin reduces sodium reabsorption and blood pressure by inhibiting the interaction between NCC and ezrin in the distal convoluted tubules of salt-loaded hypertensive mice.

Methods: Male diabetic db/db mice were salt loaded to induce hypertension and then given dapagliflozin or vehicle by oral gavage. The mice were subject to metabolic cage experiments and blood pressure was assessed using the tail-cuff method to study the impact of dapagliflozin compared to the vehicle. Protein expression of NCC and ezrin was evaluated using immunohistochemistry and Western blotting.

Results: Treatment with dapagliflozin lowered systolic blood pressure, raised urine sodium excretion, and lowered urinary potassium excretion. A decrease in phospho-NCC and ezrin proteins was observed in db/db mice treated with dapagliflozin. There was less co-localization of ezrin and phosphorylated NCC in dapagliflozin treated mice.

Conclusion: Collectively, we demonstrate that dapagliflozin reduces sodium retention and blood pressure via decreasing the density of renal NCC at the luminal membrane and the interaction between NCC and the actin cytoskeleton.

Background: Since the implementation of the Banff classification, the diagnosis and treatment of transplant rejection have been standardised. However, the rigid categorisation of transplant pathology has limited our perspective on allograft inflammation, particularly disregarding those inflammatory infiltrates who do not reach the category of rejection.

Summary: The term subclinical inflammation was introduced to designate the inflammation found in protocol biopsies, without significant renal function deterioration. Following the introduction of modern immunosuppression with tacrolimus and mycophenolate, subclinical rejection rate decreased, and less attention was paid to this entity. However, in the last decades, several studies have evaluated the impact of lower levels of inflammation and demonstrated its negative consequences on long-term outcomes. Although, in some patients, this subclinical inflammation is not permanent and can spontaneously disappear. The uncomplete definition of subclinical inflammation, which only considers renal function stability, and the evaluation of the biopsy as a definitive diagnosis, and not as a picture of an evolving process, are the main reasons why managing this inflammation represents a challenge, especially when there is no pathogenic mechanism identified.

Key messages: In this review, we revise the "natural" history of inflammation in the kidney allograft and its possible origins based on cellular composition and transcriptomic expression changes in kidney biopsies. In addition, we propose an updated definition and an approach to manage it.

Background: The recurrence of primary glomerulonephritis (GN) following kidney transplantation poses a significant threat to graft survival. To enhance kidney transplant outcomes, we must lessen the burden of recurrence. In recent years, there has been progress in understanding the incidence, risk factors for recurrence, pathophysiology, biomarkers, and therapeutics, making it worthwhile to conduct an update on primary GN that may recur following kidney transplantation.

Summary: We conducted a narrative review of the literature on the novel discoveries of primary GN that can recur following kidney transplantation. To summarize, developing a broad consensus on recurrence diagnosis would greatly advance our understanding, and its development would be a valuable collaborative effort. The key risk factors for recurrence have been better understood, particularly in individuals with complement-related or monoclonal gammopathy-related recurrent membranoproliferative GN. Furthermore, we can identify better recurrent IgA nephropathy patients who are more likely to experience graft loss. New biomarkers for membranous nephropathy (anti-PLA2R-Ab) and focal and segmental glomerulosclerosis (anti-nephrin-Ab) can assist in identifying and monitoring patients at risk of recurrence. Regarding therapy, the focal and segmental glomerulosclerosis consensus will enhance recurrence treatment. Some complement inhibitors and anti-CD38 monoclonal antibodies are already promising in treating and healing recurrent C3 glomerulopathy and focal and segmental glomerulosclerosis, respectively. Finally, new drugs developed specifically to treat IgA nephropathy in the native kidney will also change the outcome of IgA nephropathy recurrence.

Key messages: Although there has been progress in understanding the recurrence of primary GN following kidney transplantation, a worldwide effort should be undertaken to gather research that will allow for improved diagnosis, monitoring, and management of these patients.

Background: Kidney disease poses a significant global health challenge, marked by a rapid decline in renal function due to a variety of causative factors. A crucial element in the pathophysiology of kidney disease is the dysregulation of epithelial cells, which are vital components of renal tissue architecture. The integrity and functionality of these cells are largely dependent on tight junctions (TJ) proteins, complex molecular structures that link adjacent epithelial cells. These TJ not only confer cellular polarity and maintain essential barrier functions but also regulate epithelial permeability.

Summary: TJ proteins are pivotal in their traditional role at cell junctions and in their non-junctional capacities. Recent research has shifted the perception of these proteins from mere structural elements to dynamic mediators of kidney disease, playing significant roles in various renal pathologies. This review explores the multifaceted roles of TJ proteins, focusing on their functions both within and external to the renal epithelial junctions. It highlights how these proteins contribute to mechanisms underlying kidney disease, emphasizing their impact on disease progression and outcomes.

Key messages: TJ proteins have emerged as significant players in the field of nephrology, not only for their structural role but also for their regulatory functions in disease pathology. Their dual roles in maintaining epithelial integrity and mediating pathological processes make them promising therapeutic targets for kidney disease. Understanding the intricate contributions of TJ proteins in kidney pathology offers potential for novel therapeutic strategies, aiming to modulate these proteins to halt or reverse the progression of kidney disease.

Background: Previous studies have linked primary aldosteronism to simple renal cysts (SRCs), but the relationship between plasma aldosterone concentration (PAC) and SRC remains unclear. This study aimed to investigate the association between PAC and SRC in hypertensive patients.

Methods: A total of 30,135 hypertensive patients who visited our hospital from January 2014 to December 2023 were included. Logistic regression analyses were conducted to explore the relationship between PAC and SRC, while restricted cubic splines (RCS) assessed the dose-response relationship. SRC were further categorized by size (≥2 cm) and number ≥2). Subgroup analyses were performed to evaluate PAC effects across different conditions.

Results: Multivariate logistic regression showed a positive association between PAC levels (per 5-ng/dL increase) and SRC (OR: 1.20, 95% CI: 1.17-1.23) after adjusting for confounders. Compared to the lowest PAC quartile (Q1), the Q2, Q3, and Q4 groups had progressively higher risks of SRC, with ORs of 1.03 (95% CI: 0.95-1.12), 1.25 (95% CI: 1.15-1.35), and 1.65 (95% CI: 1.52-1.78), respectively. Combining Q3 and Q4 (PAC ≥14.92) yielded an OR of 1.41 compared to Q1 and Q2 (<14.92). Similar trends were observed for SRC size ≥2 cm and number ≥2. RCS analysis confirmed a linear dose-response relationship between PAC and SRC risk. Subgroup and sensitivity analyses consistently supported these findings.

Conclusions: Elevated PAC levels have been linked to an increased risk of SRC in hypertensive patients. Regulating PAC levels may help mitigate SRC formation; however, further prospective studies are required to confirm this causal relationship.

Background: The cellular proteostasis machinery is essential for maintaining protein homeostasis by employing quality control systems that identify, sequester, and eliminate damaged or misfolded proteins. However, the accumulation of misfolded proteins can overwhelm these protective mechanisms, disrupting proteostasis. This phenomenon is a hallmark of numerous pathologies, including a variety of genetic disorders. In the secretory pathway, the buildup of misfolded proteins triggers endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR). The UPR serves as an adaptive mechanism, aiming to alleviate stress and restore cellular homeostasis. However, if ER stress is prolonged or severe, the UPR may fail to restore balance and apoptosis is induced.

Summary: This review introduces the intricate signaling pathways activated by the three UPR transmembrane sensors: protein-kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). We briefly present the roles of the distinct transcriptional programs activated by each sensor in modulating the cellular response to protein stress and in determining cell fate. We discuss how genetic variants and environmental factors contribute to the heterogeneity observed in protein misfolding diseases. Finally, we critically evaluate select therapeutic strategies, specifically protein stabilization, trafficking modulation, and UPR sensor targeting approaches.

Key messages: This review introduces the potential consequences of protein misfolding, which may not only impair protein function but can also lead to toxic protein accumulation and stress induction. Using Fabry disease as a compelling example, we suggest that future therapeutic intervention may require nuanced, combination approaches that address both loss and gain of protein function.

Background: Artificial intelligence, initiated in the 1950s, has matured after two setbacks into deep neural networks (DNNs) and large language models (LLMs). Key drivers of success were the adoption of nonlinear models and autonomous learning. DNNs function as discriminative models that hierarchically interpret features to classify images, while LLMs, as generative models trained on vast datasets, generate text based on contextual meaning.

Summary: Digital pathology (DP) employing DNNs and LLMs is advancing globally, yet Japan lags behind. To standardize diagnostic interpretation and reduce the workload of pathologists, integration of DP into renal transplant pathology (RTP) is essential. The CAMELYON16 challenge demonstrated that AI can achieve diagnostic accuracy comparable to or surpassing expert pathologists. In the USA, over ten DP systems have been approved by the FDA as class II medical devices for primary diagnosis. Moreover, US law assigns liability for AI-related misdiagnosis jointly to pathologists and institutions, promoting both accuracy and legal protection for pathologists. In 2019, the Banff Digital Pathology Working Group was established to build a pathology repository, share AI algorithms, and foster model standardization through competitions. With numerous AI systems emerging, DP platforms should evolve in parallel with biennial Banff classification updates.

Key messages: AI in RTP can enhance diagnostic objectivity and alleviate pathologists' workload. Linking Banff updates with AI retraining enables continuously updated, globally standardized DP. Advanced DP requires close collaboration between transplant pathologists, AI engineers, and cutting-edge graphics processing unit resources.