Nephron最新文献

Introduction: Renal involvement in TAFRO syndrome usually is present as acute kidney injury with oligoproteinuria. Renal pathology is typically characterized by glomerular microangiopathy without immune deposits, and there have been no reports of membranous nephropathy. While idiopathic multicentric Castleman disease (iMCD), which shares a similar pathophysiology with TAFRO syndrome, has documented several cases of membranous nephropathy, the underlying mechanisms remain unclear.

Case presentation: We present a case of TAFRO syndrome presenting with nephrotic syndrome, and kidney biopsy revealed exostosin 1/exostosin 2 (EXT1/EXT2)-associated membranous nephropathy. EXT1/EXT2 is considered a potential target antigen in autoimmune membranous nephropathy, suggesting their potential pathogenic role in this case. In iMCD cases with membranous nephropathy, IL-6 levels tend to be slightly low, while VEGF levels are significantly elevated, as seen in the present case. This cytokine profile may contribute to the differences in renal pathological findings and may also be involved in the response to treatment.

Conclusion: This case may enhance our understanding of the pathophysiology of membranous nephropathy in TAFRO syndrome and iMCD.

Introduction: Renal ciliopathy is a genetic disorder caused by abnormalities in primary cilia. Alström syndrome (AS) is a rare renal ciliopathy caused by mutations in the ALMS1 gene. The diagnostic criteria for AS include symptoms such as vision impairment, obesity, type 2 diabetes, hearing loss, and renal failure. The manifestations of these symptoms vary widely, making the diagnosis of AS difficult.

Case presentation: We report the case of a 31-year-old Japanese woman and her 1 year older brother with cone-rod dystrophy (retinal degeneration) and end-stage kidney disease (ESKD), who presented with a clinical course similar to that of AS. Exome sequencing revealed two shared missense variants in ALMS1: c.4334A>T in exon 8 and c.7976C>G in exon 10. In silico analysis suggested that c.4334A>T was likely benign, whereas c.7976C>G was interpreted as a variant of uncertain significance (VUS). A definitive diagnosis of AS could not be made because typical symptoms such as diabetes and obesity were absent. Renal pathological findings in the proband's brother showed tubulointerstitial nephritis and shortening of the proximal tubule cilia, consistent with the known pathological features of AS. The rare and shared clinical features observed in both siblings suggest that VUS is associated with a partial manifestation of AS.

Conclusion: Both siblings presented with two rare clinical features, cone-rod dystrophy and ESKD, at a young age and carried the same VUS in ALMS1, suggesting the possibility of a partial AS.

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.