Frontiers in nephrology最新文献

Urine electrolytes and indices assessment as a tool for acute kidney injury (AKI) pathophysiological understanding and management is, until these days, a matter of debate. The classic division of AKI in "pre-renal" (functional/transient) and "renal" (structural/persistent) based on the urinary concentration of sodium and the fractional excretions of sodium and urea has gained popularity for decades and is still present in medical textbooks. Nevertheless, the conclusions of the studies that have used these parameters are very heterogenous and controversial. In the last decade, the pre-renal paradigm has been questioned since urine biochemistry (UB) compatible with "pre-renal AKI" was retrieved from experimental animals with increased renal blood flow, leading some authors to conclude that this approach is not useful for AKI monitoring. Our group has also studied the use of UB in AKI and we think that the key point for adequate use of this tool in clinical practice is a complete mindset change in the way we look and interpret data. In this article, we present the "urine biochemical approach" as an alternative way for UB assessment, which we believe that makes more sense and seems to be more useful for AKI monitoring than the traditional approach. Although the real utility of this alternative approach needs to be confirmed in large, prospective studies, the aim of the present article is to open the mind of critical care practitioners for a potential reappraisal of ancient concepts and ideas regarding the use of urine electrolytes in AKI monitoring.

Acute kidney injury (AKI) in pediatric and neonatal populations poses significant diagnostic and management challenges, with delayed detection contributing to long-term complications such as hypertension and chronic kidney disease. Recent advancements in artificial intelligence (AI) offer new avenues for early detection, risk stratification, and personalized care. This paper explores the application of AI models, including supervised and unsupervised machine learning, in predicting AKI, improving clinical decision-making, and identifying subphenotypes that respond differently to interventions. It discusses the integration of AI with existing risk scores and biomarkers to enhance predictive accuracy and its potential to revolutionize pediatric nephrology. However, barriers such as data quality, algorithmic bias, and the need for transparent and ethical implementation are critical considerations. Future directions emphasize incorporating biomarkers, expanding external validation, and ensuring equitable access to optimize outcomes in pediatric AKI care.

Primary IgA nephropathy (IgAN) is the most common form of primary glomerulopathy. A slowly progressive disease presenting in the young to middle-aged, most patients with reduced eGFR or proteinuria will progress to end-stage kidney disease (ESKD) in their lifetimes. The pathogenesis involves increased production of galactose-deficient IgA1 (Gd-IgA1) that forms immune complexes that deposit in the glomerulus, eliciting mesangial cell proliferation, inflammation, and complement activation. The backbone of therapy is supportive, including lifestyle modifications, strict blood pressure control, and renin-angiotensin system inhibition targeting proteinuria < 300 mg/day. Sodium-glucose transporter 2 inhibitors are indicated for persisting proteinuria or declining eGFR. Sparsentan is indicated for persisting proteinuria. Immunosuppression should be considered for all patients at risk for progression (persisting proteinuria and/or declining eGFR). To reduce Gd-IgA1 production, targeted-release budesonide is approved. Agents targeting B cell survival factors APRIL or BAFF/APRIL have significantly reduced Gd-IgA1 production and proteinuria in phase 2 trials but await phase 3 data for approval. To reduce inflammation, high-dose steroids are ineffective and toxic in Caucasian patients, although lower-dose regimens may be effective in Chinese patients. Complement inhibition is being actively studied. The factor B inhibitor iptacopan has conditional approval. The terminal pathway inhibitors cemdisiran and ravulizumab show promise in phase 2 studies. Our current approach for those requiring immunosuppression involves combining the reduction of Gd-IgA1 (nefecon) with suppressing the effects of inflammation (iptacopan). The optimal duration of such therapy is uncertain. Clearly, there is more to be learned with many trials underway.

Background: Steroid-resistant nephrotic syndrome (SRNS) is a rare kidney disease commonly characterized histopathologically by focal and segmental glomerulosclerosis (FSGS) or minimal change disease. One-third of SRNS-FSGS cases are attributed to a genetic cause ultimately leading to end-stage kidney disease (ESKD) during childhood or adulthood. ACTN4 variants, although rare, typically manifest in early adulthood as SRNS-FSGS with autosomal dominant inheritance pattern and are associated with variable progression toward ESKD.

Case–diagnosis/treatment: A 10-year-old Chilean male patient, born to a complicated pregnancy without any history of prenatal care, was incidentally found to have mild proteinuria during pre-surgery analysis. He was diagnosed with nephrotic syndrome and treatment with prednisone was started, but 12 months later, he persisted with hyperlipidemia, hypoalbuminemia, and proteinuria. Within a few weeks, proteinuria rapidly increased, and a kidney biopsy exhibited FSGS features. At the age of 12, he reached ESKD and initiated peritoneal dialysis, experiencing an episode of posterior reversible encephalopathy syndrome. Exome sequencing identified a novel variant of uncertain significance (VUS), ACTN4 c.625_633del that predicted the in-frame deletion p.L209_E211del in a highly conserved functional domain. He requested to be considered for kidney transplantation and the VUS in ACTN4 was re-analyzed to assess potential risks, resulting in a reclassification as likely pathogenic (PM1+PM2+PM4 criteria). At 14 years old, he received a deceased donor kidney allograft without recurrence during the subsequent 5 months.

Conclusions: Identifying VUS is a recurring challenge in routine clinical genetics, particularly for patients with rare diseases or atypical phenotypes in underrepresented populations. This case underscores the benefit of timely genetic diagnosis taking into account the patient's request. VUS reassessment becomes more relevant when considering a kidney transplant not only as an appropriate procedure, but as the therapy of choice, especially considering the patient's history of complications with variable long-term consequences.

Background: Homocysteine (Hcy) is a risk factor for stroke. In this study, we investigated the relationship between gene polymorphisms, particularly SLCO1B1 and homocysteine (Hcy) concentrations in ischemic stroke patients, with a focus on identifying potential risk factors for elevated Hcy levels.

Methods: A total of 177 ischemic stroke patients, including 99 with single nucleotide polymorphisms (SNPs), underwent pharmacogenomics (PGx) sequencing tests, from September 2022 to November 2023 at the hospital. Logistic regression analysis was used to analyze the relationship between clinical characteristics, SNPs, and Hcy concentrations. In the sub-study, 207 ischemic stroke and 244 non-stroke patients underwent SLCO1B1c.521T>C polymorphism to further demonstrate the role of SLCO1B1c.521T>C polymorphism and homocysteine.

Results: Higher Hcy concentrations were observed in men compared to women. Univariate logistic analysis identified gender, GGT concentrations, B12 concentrations, folic acid concentrations, and SLCO1B1 c.521 CC+CT polymorphism as risk factors for elevated Hcy. Multivariate logistic analysis confirmed that B12 concentrations, folic acid concentrations, and SLCO1B1 CT + CC polymorphism were significant dependent risk factors. In the sub-study, SLCO1B1 CT + CC polymorphism and the male sex were identified as risk factors for Hcy, with the effect of SLCO1B1 polymorphism being more pronounced in men.

Conclusion: Folic acid and vitamin B12 reduce Hcy concentrations, while the SLCO1B1 CT and CC polymorphisms are associated with higher Hcy levels. The impact of SLCO1B1 gene polymorphism on Hcy is notably stronger in the male population, suggesting that genetic factors play a significant role in determining Hcy levels.

Background: Glomerular diseases significantly impact global health. This study investigated public interest in five common glomerular diseases.

Methods: Google Trends™ were used to analyze search activity from January 2004 to December 2024 for IgA nephropathy (IgAN), membranous glomerulonephritis (MN), focal segmental glomerulosclerosis (FSGS), lupus nephritis (LN), and diabetic nephropathy (DN). Data were retrieved both globally and in English-speaking countries, including the United States. Monthly and yearly relative search activity were assessed and compared.

Results: Globally, IgAN had the highest average relative search activity, followed by DN, FSGS, LN, and MN. Both IgAN and FSGS exhibited declining trends, while LN showed an upward pattern. MN and DN experienced a modest decline before 2016, preceded by a slight increase. Among English-speaking countries, search interest was predominantly concentrated in five countries, primarily including the United States, United Kingdom, Canada, and Australia, with the United States consistently ranking as the leading country. For IgAN, LN, and MN, the trends observed in the United States appeared to align with global data. In contrast, search interest for FSGS exceeded global levels, while interest in DN was slightly lower than global activity. In the United States, IgAN, FSGS, and LN were most prominent in North Dakota, Massachusetts, and Delaware, respectively, while DN and MN saw peak activity in West Virginia.

Conclusion: Public engagement with glomerular diseases has not uniformly grown, at least in English-speaking countries, emphasizing the need for enhanced awareness efforts. Future analysis should prioritize search terms in the predominant language of each country.

Background: This study assesses the impact of human leukocyte antigen (HLA)-DR mismatch and donor-estimated glomerular filtration rate (eGFR) on outcomes of living donor kidney transplantation (LDKT), which are especially relevant to the availability of multiple donors and paired kidney exchanges.

Methods: Using data from the Scientific Registry of Transplant Recipients (SRTR), we retrospectively analyzed graft survival in adult LDKT recipients transplanted between January 2013 and September 2022. Recipients with 0 HLA-DR mismatches were compared to those with 1-2 HLA-DR mismatches. Cox models assessed the association between donor eGFR and graft and patient survival, stratifying by a) HLA-DR mismatches, and b) HLA-DR mismatches and recipient age.

Results: Among 44,080 recipients, 7,195 had 0 HLA-DR mismatches and 36,885 had 1-2 HLA-DR mismatches. The recipients' mean age was 49.1 for the 0 HLA-DR mismatch group and 50.4 for the 1-2 HLA-DR mismatch group. The donors' mean age was 43.1 and 43.8, with an eGFR of 101.0 and 99.9 ml/min, respectively. A higher donor eGFR was associated with better graft survival. Stratified analyses showed higher donor eGFR levels reduced the risk of graft loss in cases with DR mismatch (p < 0.001) but not in cases without HLA-DR mismatch (p = 0.81). This effect was significant for recipients aged 18-39 and over 60. Similar results were observed for patient survival.

Conclusions: Higher donor eGFR was associated with lower risks of graft loss and patient death in the HLA-DR mismatch group but not the 0 HLA-DR mismatch group. These results emphasize the importance of considering both HLA-DR matching and donor kidney function, particularly for younger recipients to avoid sensitization for future transplants.

Introduction: Antiretroviral therapy (ART) increases the life expectancy of persons living with HIV (PLWH), but not without potentially serious adverse effects. Tenofovir disoproxil fumarate (TDF) can cause nephrotoxicity, manifesting as acute kidney injury (AKI) that may persist after treatment discontinuation. Kidney injury biomarkers such as kidney injury molecule-1 (KIM-1), retinol-binding protein-4 (RBP-4), interleukin-18 (IL-18), and neutrophil gelatinase-associated lipocalin (NGAL) can aid early diagnosis and predict TDF-associated nephrotoxicity. This study aimed to determine whether the change from baseline in urine KIM-1 (δKIM-1) and NGAL (δNGAL) following 2 weeks of TDF use could predict subclinical TDF-associated nephrotoxicity before the overt manifestation as acute kidney disease after 3 months.

Methods: A prospective cohort study of 205 PLWH was conducted at the Adult Center for Infectious Disease Research (AIDC) in Lusaka, Zambia. ART-naïve PLWH who were starting treatment with TDF with intact kidney function [estimated glomerular filtration rate (eGFR)> 60 mL/min/1.73m²] were followed at initiation, 2 weeks, and approximately 3 months to determine the incidence of TDF-associated nephrotoxicity. We measured urine KIM-1 and NGAL at baseline and after 2 weeks of treatment to determine if it predicted subclinical nephrotoxicity. The presence of TDF-associated nephrotoxicity was defined according to the established acute kidney disease and disorders criteria (AKD) as having either 1) one or more episodes of eGFR< 60ml/min/1.73m² within 3 months, 2) a reduction in eGFR of greater than 35% (from baseline) within 3 months, and/or 3) an increase in serum creatinine of more than 50% (from baseline) within 3 months.

Results: The incidence of TDF-associated nephrotoxicity was 22%. Baseline eGFR, creatinine, age, female sex, and BMI predicted the risk of overt TDF-associated nephrotoxicity. The median baseline KIM-1-to-creatinine and NGAL-1-to-creatinine ratios of the participants who developed overt TDF-associated nephrotoxicity and those who did not were not significantly different. However, every 1 pg/mg increase in δKIM-1 was associated with a 41% higher risk of TDF-associated nephrotoxicity. No association was observed with δNGAL.

Conclusions: The incidence of TDF-associated nephrotoxicity was high. Change in KIM-1 level within 2 weeks of the initiation of TDF treatment predicted subclinical TDF-associated nephrotoxicity before overt manifestation as acute kidney disease while δNGAL within the same period did not predict subclinical TDF-associated nephrotoxicity.

In glomerulopathies, endothelial dysfunction and the presence of histological vascular lesions such as thrombotic microangiopathy, arteriolar hyalinosis, and arteriosclerosis are related to a severe clinical course and worse renal prognosis. The endothelial cell, which naturally has anti-inflammatory and anti-thrombotic regulatory mechanisms, is particularly susceptible to damage caused by various etiologies and can become dysfunctional due to direct/indirect injury or a deficiency of protective factors. In addition, endothelial regulation and protection involve participation of the complement system, factors related to angiogenesis, the renin-angiotensin system (RAS), endothelin, the glycocalyx, the coagulation cascade, interaction between these pathways, interactions between glomerular structures (the endothelium, mesangium, podocyte, and basement membrane) and interstitial structures (tubules, arterioles and small vessels). Dysregulation of those components is also associated with the progression of renal fibrosis, since endothelial cell damage promotes endothelial-to-mesenchymal transition. Although the potential mechanisms of vascular injury have been widely described in diabetic kidney disease, hypertensive nephrosclerosis, and hemolytic uremic syndrome, they require further elucidation in other glomerulopathies. A better understanding of the pathogenesis of vascular injury in patients with glomerular diseases could contribute to the development of specific treatments for such injury.