Nephron最新文献

Background: Chemokines orchestrate immune cells activation and infiltration during acute kidney injury (AKI).

Objectives: We aim to test whether deletion of C-C chemokine ligand 7 (CCL7), a small chemokine related to CCL2 (MCP-1), may modulate AKI development and progression toward kidney fibrosis.

Method: Expression of CCL7 was quantified in murine cortical tubular (MCT) cells exposed to myoglobin or lipopolysaccharide or submitted to metabolic reprogramming. Kidney function (BUN, glomerular filtration rate), expression of CCL7 receptors, and kidney infiltration by inflammatory cells (F4/80+ macrophages, MPO+ neutrophils, and B220+ B-cells) were assessed in wt and Ccl7-/- mice submitted to 3 different models of AKI or kidney fibrosis (uni/bilateral ischemia/reperfusion injury (u/bIRI) and rhabdomyolysis).

Results: Toxin exposure of MCT cells, as well as metabolic reprogramming recapitulating AKI changes, led to a dramatic up-regulation of CCL7. In vivo, kidney expression of Ccl7 and Ccl2 significantly increased after AKI and remained increased beyond the acute phase (30 days after uIRI). The expression of the CCL7 receptors was heterogeneous and varied with time. Kidney function, expression of CCL7 receptors and Ccl2, and the number of inflammatory cells within kidneys were similar in wt and Ccl7-/- mice at baseline and at day 2 after AKI. Thirty days after uIRI, kidney fibrosis was similar in both mouse strains.

Conclusions: Despite strong induction of CCL7 after AKI, CCL7 deficiency does not prevent AKI and the transition toward kidney fibrosis and should probably not be further explored as a potential target to prevent or treat AKI.

Introduction: ob/ob mice are a leptin-deficient type 2 diabetes mellitus model, which, on a BTBR background, mimics the glomerular pathophysiology of diabetic nephropathy (DN). Since leptin deficiency reduces blood pressure (BP) and endothelial nitric oxide synthase (eNOS) lowers BP and is kidney protective, we attempted to develop a more robust DN model by introducing eNOS deficiency in BTBR ob/ob mice.

Methods: Six experimental groups included littermate male and female BTBR ob/ob or wild-type for ob (control) as well as wild-type (WT), heterozygote (HET), or knockout (KO) for eNOS. Systolic BP (by automated tail-cuff) and GFR (by FITC-sinistrin plasma kinetics) were determined in awake mice at 27-30 weeks of age, followed by molecular and histological kidney analyses.

Results: Male and female ob/ob WT presented hyperglycemia and larger body and kidney weight, GFR, glomerular injury, and urine albumin to creatinine ratio (UACR) despite modestly lower BP versus control WT. These effects were associated with a higher tubular injury score and renal mRNA expression of NGAL only in males, whereas female ob/ob WT unexpectedly had lower KIM-1 and COL1A1 expression versus control WT, indicating sex differences. HET for eNOS did not consistently alter BP or renal outcome in control or ob/ob. In comparison, eNOS KO increased BP (15-25 mm Hg) and worsened renal markers of injury, inflammation and fibrosis, GFR, UACR, and survival rates, as observed in control and, more pronouncedly, in ob/ob mice and independent of sex.

Conclusions: Deletion, but not heterozygosity, of eNOS raises blood pressure and aggravates nephropathy in BTBR ob/ob mice.

Background: Infections with B.1.1.529 (Omicron) variants of SARS-CoV-2 became predominant worldwide since late 2021, replacing the previously dominant B.1.617.2 variant (Delta). While those variants are highly transmissible and can evade vaccine protection, population studies suggested that outcomes from infection with Omicron variants are better compared with Delta. Data regarding prognosis of maintenance hemodialysis (MHD) patients infected with Omicron versus Delta variants, however, are scarce.

Methods: This retrospective cohort study includes all patients with end-stage kidney disease treated with MHD in Meir Medical Center, Kfar-Saba, Israel, that were diagnosed with SARS-CoV-2 infection between June 2021 and May 2022.

Results: Twenty-six subjects were diagnosed with the Delta variant and 71 with Omicron. Despite comparable age between groups and higher mean vaccine doses prior to the infection among the Omicron group (p < 0.001), SARS-CoV-2 infection severity was significantly worse among MHD infected with the Delta variant: 50% developed severe or critical COVID-19 versus 5% in the Omicron group (p < 0.001). Over half of MHD infected with Omicron (57%) were asymptomatic during their illness. The 30-day mortality rate for the whole cohort was 5.2%. It was significantly higher among MHD in the Delta group than in the Omicron group (5/26, 19.2% vs. 0/71, p < 0.001), as was the 90-day mortality rate (5/26, 19.2% vs. 3/71, 4.2%, p = 0.02).

Conclusions: Infection with the SARS-CoV-2 Delta variant was associated with worse outcomes compared with Omicron, among subjects on MHD. However, despite mild disease among vaccinated MHD patients, infection with Omicron variant was still associated with the significant 90-day mortality rate.

Objective: Myostatin, which is known as a negative skeleton muscle regulator, is associated with mortality in maintenance hemodialysis patients. However, the significance of serum myostatin concentrations at dialysis initiation has not been established. We investigated the relation between serum myostatin concentrations and mortality or hospitalization within 1 year in incident dialysis patients.

Methods: After a patient initiating hemodialysis or peritoneal dialysis during 2016-2018 was enrolled, the patient's serum myostatin at dialysis initiation was measured. Composite outcomes comprising mortality and hospitalization within 1 year after dialysis initiation were compared between two groups divided according to myostatin levels. The Cox proportional hazards model was used to assess significant relations between myostatin and outcomes.

Results: This study examined 104 incident dialysis patients with a mean age of 65.5 ± 14.0 years (68% male). Kaplan-Meier analyses indicated the 1-year hospitalization-free and survival rate as significantly lower in the lower myostatin group than in the higher myostatin group (p = 0.0020). Cox proportional hazards regression analyses revealed that the value of myostatin logarithm at dialysis initiation was inversely associated with the occurrence of a composite outcome, independently of age (hazard ratio 0.16, 95% confidence interval: 0.05-0.57). Receiver operating characteristic analysis showed the area under the curve of serum myostatin for predicting death or hospitalization within 1 year as higher than those of clinical indices of nutritional disturbance and frailty.

Conclusion: Serum myostatin concentration at dialysis initiation is inversely associated with adverse outcomes in these dialysis-initiated patients.

Although glomerular damage caused by diabetic nephropathy was thought to be irreversible, in recent years, there have been reports on improvement in glomerular damage with strict glycemic control. However, few reports are available on the pathologic course after renal transplantation of donor-derived grafts with findings of diabetic nephropathy. A 53-year-old woman underwent an ABO blood-type compatible living-donor renal transplant. The recipient had no history of diabetes, and fasting blood glucose and hemoglobin A1c levels were both normal. The donor was a 57-year-old male who had received treatment for type 2 diabetes mellitus for 10 years. Transplant renal biopsy performed 1 h after revascularization showed mesangial matrix expansion and arterial hyalinosis due to diabetic nephropathy. The blood glucose level was within the normal range after transplantation. Mesangial matrix expansion and arterial hyalinosis disappeared in allograft biopsy samples 7 years after transplantation. We observed significant improvement in the pathological findings of donor-derived diabetic nephropathy after renal transplantation in the subsequent follow-ups.

Collapsing glomerulopathy (CG) is a rare glomerular disease and its familial form is even rarer. CG and non-collapsing forms of focal segmental glomerulosclerosis may both be caused by pathogenic variants in the same genes, but there is less information on genetics of the former disease. We hypothesized that different hits (viral infection and genetic variants) may be involved in the development of a familial CG here described. We performed renal and etiological routine evaluation, PVB19 serology, genetic tests including whole-exome analysis and dosage of serum thrombomodulin (THBD) in two siblings with CG, one healthy sister, and their mother. The THBD gene variant p.A43T in homozygosity was identified in the proband and her affected brother, both with CG. The same mutation was identified in their mother in heterozygosity. THBD levels were elevated in the serum of both affected siblings. They also had PVB19 positive serology and the G1 high-risk apolipoprotein L1 (APOL1) alleles in homozygosity. Their healthy sister had no PVB19-positive serology and no THBD nor APOL1 gene variants. In this case of familial CG, THBD, and APOL1 gene variants, and a previous PVB19 infection may be associated with the development of CG in a multihit process. In addition, the p.A43T THBD variant, identified in the affected siblings, has never been previously described in homozygosis, pointing to a likely autosomal recessive CG trait caused by this gene mutation.

Introduction: This study aimed to investigate the efficacy and safety of sucroferric oxyhydroxide (SFOH) versus sevelamer carbonate in controlling serum phosphorus (sP) in adult Chinese dialysis patients with hyperphosphataemia (sP >1.78 mmol/L).

Methods: Open-label, randomised (1:1), active-controlled, parallel group, multicentre, phase III study of SFOH and sevelamer at starting doses corresponding to 1,500 mg iron/day and 2.4 g/day, respectively, with 8-week dose titration and 4-week maintenance (NCT03644264). Primary endpoint was non-inferiority analysis of change in sP from baseline to week 12. Secondary endpoints included sP over time and safety.

Results: 415 patients were screened; 286 were enrolled and randomised (142 and 144 to SFOH and sevelamer, respectively). Mean (SD) baseline sP: 2.38 (0.57) and 2.38 (0.52) mmol/L, respectively. Mean (SD) change in sP from baseline to week 12: - 0.71 (0.60) versus -0.63 (0.52) mmol/L, respectively; difference (sevelamer minus SFOH) in least squares means (95% CI): 0.08 mmol/L (-0.02, 0.18) with the lower limit of 95% CI above the non-inferiority margin of -0.34 mmol/L. The SFOH group achieved target sP (1.13-1.78 mmol/L) earlier than the sevelamer group (56.5% vs. 32.8% at week 4) and with a lower pill burden (mean 3.7 vs. 9.1 tablets/day over 4 weeks of maintenance, respectively). Safety and tolerability of SFOH was consistent with previous studies, and no new safety signals were observed.

Conclusion: SFOH effectively reduced sP from baseline and was non-inferior to sevelamer after 12 weeks of treatment but had a lower pill burden in Chinese dialysis patients with hyperphosphataemia; SFOH benefit-risk profile is favourable in Chinese patients.

Background: Due to the complexity of chronic kidney disease (CKD) pathophysiology, biomarkers representing different mechanistic pathways have been targeted for the study and development of novel biomarkers. The discovery of clinically useful CKD biomarkers would allow for the identification of those children at the highest risk of kidney function decline for timely interventions and enrollment in clinical trials.

Summary: Glomerular filtration rate and proteinuria are traditional biomarkers to classify and prognosticate CKD progression in clinical practice but have several limitations. Over the recent decades, novel biomarkers have been identified from blood or urine with metabolomic screening studies, proteomic screening studies, and an improved knowledge of CKD pathophysiology. This review highlights promising biomarkers associated with the progression of CKD that could potentially serve as future prognostic markers in children with CKD.

Key messages: Further studies are needed in children with CKD to validate putative biomarkers, particularly candidate proteins and metabolites, for improving clinical management.

Introduction: NEUTRALIZE-AKI is a pivotal study to evaluate the safety and effectiveness of the selective cytopheretic device (SCD) in adult patients with acute kidney injury (AKI) requiring continuous kidney replacement therapy (CKRT).

Methods/design: This is a two-arm, randomized, open-label, controlled multi-center pivotal US study which will enroll 200 adult patients (age 18-80 years) in the intensive care unit with acute kidney injury requiring CKRT and at least one additional organ failure across 30 clinical centers. Eligible patients will be randomized to CKRT plus SCD therapy versus CKRT alone. Therapy will be administered for up to 10 days, with the hypothesis that the CKRT plus SCD group will demonstrate a lower mortality rate or better rate of renal recovery than the CKRT alone group by day 90. The primary outcome is a composite of dialysis dependence or all-cause mortality at day 90.

Conclusion: The SCD is a cell-directed extracorporeal therapy that targets and deactivates pro-inflammatory neutrophils and monocytes, with evidence of efficacy across a variety of critically ill patient populations. Knowledge and experience from many of those studies and other AKI trials were incorporated into the design of this pivotal study, with the aim to investigate the role of effector cell immunomodulation in the intervention of AKI.

Background: Bile acids (BAs) act not only as lipids and lipid-soluble vitamin detergents but also function as signaling molecules, participating in diverse physiological processes. The identification of BA receptors in organs beyond the enterohepatic system, such as the farnesoid X receptor (FXR), has initiated inquiries into their organ-specific functions. Among these organs, the kidney prominently expresses FXR.

Summary: This review provides a comprehensive overview of various BA species identified in kidneys and delves into the roles of renal apical and basolateral BA transporters. Furthermore, we explore changes in BAs and their potential implications for various renal diseases, particularly chronic kidney disease. Lastly, we center our discussion on FXR, a key BA receptor in the kidney and a potential therapeutic target for renal diseases, providing current insights into the protective mechanisms associated with FXR agonist treatments.

Key messages: Despite the relatively low concentrations of BAs in the kidney, their presence is noteworthy, with rodents and humans exhibiting distinct renal BA compositions. Renal BA transporters efficiently facilitate either reabsorption into systemic circulation or excretion into the urine. However, adaptive changes in BA transporters are evident during cholestasis. Various renal diseases are accompanied by alterations in BA concentrations and FXR expression. Consequently, the activation of FXR in the kidney could be a promising target for mitigating kidney damage.