Nephron最新文献

Introduction: Among patients on hemodialysis (HD), physical frailty and sleep disturbances are not only common but also associated with adverse outcomes. The aim of this study was to evaluate the association between physical frailty and sleep disturbances in patients on HD.

Methods: This cross-sectional study was conducted from June 2017 to March 2021, with outpatients receiving HD 3 times a week at two dialysis facilities in Japan. Sleep disturbances were identified with the Athens Insomnia Scale (AIS). Physical frailty was defined using the Fried Frailty Phenotype. Patients were classified as "non-frailty (number of frailty components: 0-2)" or "frailty (3-5)." We examined the association of sleep disturbances with physical frailty and its components by performing a logistic regression analysis.

Results: We analyzed 360 patients (mean age 65.6 years; 62% men). Eighty-one patients (23%) were classified into the group with frailty, and the mean AIS score was 5.2 ± 4.2 points. After adjusting for clinical characteristics, increasing the AIS score per 1 point was associated with higher odds of physical frailty (odds ratio, 1.12; 95% confidence interval, 1.05-1.20; p < 0.01). As for the frailty components, exhaustion, low physical activity, and weak grip strength showed an association with sleep disturbances (all p < 0.05).

Conclusions: Sleep disturbances were independently associated with physical frailty in patients on HD. Future studies are warranted to investigate the causality between physical frailty and sleep disturbances in this population.

Introduction: Familial hyperkalemic hypertension (FHHt) is an inherited disease characterized by hyperkalemia, hypertension, and hyperchloremic acidosis (HCA). The primary defect is a hyperactive sodium chloride co-transporter, expressed in the renal distal tubule. FHHt is caused by mutation in either WNK1, WNK4, KLHL3, or Cul3. The mechanism of HCA is not completely understood.

Methods: Clinical and genetic data were collected from the largest family with FHHt described in the literature. Urine ammonia was measured in 26 family members. Epilepsy was diagnosed clinically.

Results: Of the 85 family members, 44 are affected by the Q565E WNK4 mutation, and 28 are newly described. In genetically engineered mice, urinary ammonium was decreased. In our study, urine ammonium did not change. In 11 unaffected subjects, urine ammonia per creatinine was 8.013 ± 3.620 mm/mm, and in 15 subjects affected by FHHt, it was 8.990 ± 4.300 mm/mm (p = 0.546, not significant). Due to the large family size and prolonged follow-up, rare conditions can be identified. Indeed, two children have genetic generalized epilepsy and one child has migraine. The prevalence of epilepsy is 4.545% (2/44) much higher than in the general population (0.681%). This difference is statistically significant (χ2 with Yates correction = 5.127, p = 0.023).

Conclusions: We provide further evidence that the origin of HCA in FHHt lies in the proximal renal tubule. The association of FHHt with epilepsy leads us to speculate that the raised serum K in susceptible subjects may cause a rise in CSF K, and extracellular cerebral K, leading to epilepsy.

Introduction: Several mouse models with diverse disease etiologies are used in preclinical research for chronic kidney disease (CKD). Here, we performed a head-to-head comparison of renal transcriptome signatures in standard mouse models of CKD to assess shared and distinct molecular changes in three mouse models commonly employed in preclinical CKD research and drug discovery.

Methods: All experiments were conducted on male C57BL/6J mice. Mice underwent sham, unilateral ureter obstruction (UUO), or unilateral ischemic-reperfusion injury (uIRI) surgery and were terminated two- and 6-weeks post-surgery, respectively. The adenine-supplemented diet-induced (ADI) model of CKD was established by feeding with adenine diet for 6 weeks and compared to control diet feeding. For all models, endpoints included plasma biochemistry, kidney histology, and RNA sequencing.

Results: All models displayed increased macrophage infiltration (F4/80 IHC) and fibrosis (collagen 1a1 IHC). Compared to corresponding controls, all models were characterized by an extensive number of renal differentially expressed genes (≥11,000), with a notable overlap in transcriptomic signatures across models. Gene expression markers of fibrosis, inflammation, and kidney injury supported histological findings. Interestingly, model-specific transcriptome signatures included several genes representing current drug targets for CKD, emphasizing advantages and limitations of the three CKD models in preclinical target and drug discovery.

Conclusion: The UUO, uIRI, and ADI mouse models of CKD have significant commonalities in their renal global transcriptome profile. Model-specific renal transcriptional signatures should be considered when selecting the specific model in preclinical target and drug discovery.

Medullary sponge kidney (MSK) is a description of radiographic features. However, the pathogenesis of MSK remains unclear. MSK is supposed to be the cause of secondary distal renal tubular acidosis (dRTA), although there are case reports suggesting that MSK is a complication of primary dRTA. In addition to these reports, we report 3 patients with metabolic acidosis and MSK, in whom primary dRTA is confirmed by molecular genetic analyses of SLC4A1 and ATP6V1B1 genes. With a comprehensive genetics-first approach using the 100,000 Genomes Rare Diseases Project dataset, the association between MSK and primary dRTA is examined. We showed that many patients with MSK phenotypes are genetically tested with a gene panel which does not contain dRTA-associated genes, revealing opportunities for missed genetic diagnosis. Our cases highlight that the radiological description of MSK is not a straightforward disease or clinical phenotype. Therefore, when an MSK appearance is noted, a broader set of causes should be considered including genetic causes of primary dRTA as the underlying reason for medullary imaging abnormalities.

Background: Early identification of dysfunctional arteriovenous haemodialysis (HD) vascular access (VA) is important for timely referral and intervention.

Method: We retrospectively calculated VA risk score using Vasc-Alert surveillance software technology from HD treatment sessions in 2 satellite HD units over 18 months. We included in the analysis HD patients dialysing with arteriovenous fistula or graft (AVF/G) with available Vasc-Alert data for≥ 2 months. For group one (eventful) that included patients who developed vascular access thrombosis or stenosis over the study period, we collected Vasc-Alert risk score 2 months prior to the event and, for group two (uneventful), over 5 consecutive months. Vasc-Alert technology utilises routinely collected data during HD to calculate VA risk score and triggers an alert if the score is ≥7 in 3 consecutive dialysis sessions. Patients with >2 alerts (vascular access score ≥7) per month were considered to have positive alerts.

Results: From 140 HD patients, 81 patients dialysed via AVF/G. 77/81 had available Vasc-Alert data and were included in the final analysis. Out of 17 eventful patients, 11 (64.7%) had positive alerts 2 months prior to the vascular event. Out of the 60 patients without vascular events, 20 patients (33.3%) had positive alert. Vasc-Alert's sensitivity and specificity for vascular events were 64.7% and 66.6%, respectively. Within the 6 patients with thrombosed access, 2 patients (33.3%) detected by Vasc-Alert were not detected with clinical monitoring.

Conclusion: Vascular access risk score can be a useful non-invasive vascular access surveillance method to assist clinical decision making.

Introduction: The renoprotective benefits of adding immunosuppressant therapy to corticosteroid (CS) treatment for immunoglobulin A nephropathy (IgAN) patients with less than 25% crescent formation (C1) remain uncertain, warranting further research.

Methods: A retrospective study was conducted on IgAN patients with crescent C1 lesions confirmed by renal biopsy at Xinqiao Hospital between May 1, 2017, and May 1, 2020. Patients were stratified into either the CS treatment group or the CS combined with an additional immunosuppressant therapy group. Follow-up assessments were conducted within 24 months. Propensity score analysis was used to match patients receiving CS and CS + immunosuppressant drug treatment in a 1:1 ratio. Primary outcomes included changes in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). Subgroup analyses were performed to evaluate the benefits of different populations. Composite endpoint outcomes comprised a 30% eGFR decrease, end-stage kidney disease (ESKD) necessitating dialysis or transplant, or kidney disease-related mortality. Adverse events were also compared between the two groups.

Results: 296 IgAN patients with C1 lesions were included in the analysis. Baseline characteristics indicated that IgAN patients in the CS + immunosuppressant group exhibited poorer renal function and higher UACR levels. Propensity score analysis effectively minimized the influence of baseline clinical characteristics, including age, serum creatinine, initial eGFR, UACR, and 24-h proteinuria. Both treatment groups demonstrated continuous eGFR improvement and significant UACR reduction during follow-up, especially at 6 months. However, no significant differences in eGFR and UACR reduction rates were observed between the two groups throughout the entire follow-up period, both before and after matching. Subgroup analysis revealed improved eGFR in both treatment groups, notably among patients with an initial eGFR below 90 mL/min/1.73 m2. Conversely, IgAN patients with C1 lesions and a cellular crescent ratio exceeding 50% treated with CS and immunosuppressant therapy experienced a significant improvement in renal function and a decline in urinary protein creatinine ratio. Composite endpoint outcomes did not significantly differ between the two groups, while the incidence of adverse events was comparable.

Conclusion: Our findings suggest that the addition of immunosuppressant therapy to corticosteroid monotherapy did not confer significant therapeutic advantages in patients with C1 lesions compared to CS monotherapy, although some specific patient populations appeared to derive modest benefits from this combined approach.

Context: The clinical indications for immune checkpoint inhibitors (ICIs) are rapidly expanding. However, adverse events affecting multiple organs, including kidneys leading to ICI-associated acute kidney injury (AKI), remain a significant challenge with ICI therapy. Although AKI is considered a rare complication, it can be severe and result in treatment interruption or discontinuation of ICIs. Despite a generally favorable kidney prognosis, the possibility of re-challenging ICI therapy remains a subject of debate, particularly for patients who have exhausted other treatment options or experienced severe AKI. Subject of Review: In a recent review article, Sprangers et al. provide a comprehensive overview of the possible mechanisms and clinical manifestations of ICI-associated AKI [Nat Rev Nephrol. 2022;18(12):794-805]. The authors propose a practical strategy for diagnosing and managing suspected cases of ICI-associated AKI, which includes identifying a subset of eligible patients who may be re-exposed to ICIs following an episode of AKI. Second Opinion: The authors of the review article offer several recommendations on the diagnosis and treatment of ICI-associated nephrotoxicity. While we generally agree with the recommendations proposed by the authors, it is important to acknowledge that the available data primarily rely on small retrospective studies, as the authors have recognized. In addition, there are two key questions that need be carefully addressed in future studies: (1) the optimal dose and duration of corticosteroids and the use of alternative immunosuppressive agents in patients with ICI-associated nephrotoxicity and (2) a clear guideline for restarting ICI treatment in patients with AKI who have not fully recovered their kidney function.

Neural cell adhesion molecule 1 (NCAM1) is a recently identified new antigen of membranous nephropathy (MN) mostly secondary to systemic lupus erythematosus with a low positive rate of 6.6%, and its corresponding antibody was detected in patients' sera. Here, we reported a case of NCAM1-positive lupus nephritis (class V+III) developed from MN. The patient was refractory to multiple immunosuppressive regimens but achieved remission after the application of rituximab as an add-on therapy and showed a reduction of anti-NCAM1 antibody and proteinuria.

Introduction: In phenylketonuria (PKU), toxic phenylalanine (Phe) can harm other organs beyond the brain. Furthermore, the lifelong therapy of PKU consists of consumption of increased amounts of amino-acid mixture that provoke hyperfiltration in the glomeruli. Therefore, the adherence to therapy in PKU might influence the long-term kidney function in PKU patients.

Methods: Data from 41 adult, early treated PKU patients were analyzed in this 10-year, retrospective, monocentric study. Two subgroups were created according to their therapy adherence: one with long-term blood Phe levels in the therapeutic range (<600 µmol/L), and one with suboptimal blood Phe levels. Renal function and metabolic parameters were collected over 10 years. Kidney function parameters were compared between the two groups and associations between blood Phe levels and kidney function were tested.

Results: After 10 years, serum creatinine levels (p = 0.369) and estimated glomerular filtration rate (eGFR) (p = 0.723) did not change significantly from baseline in the good therapeutic group. The suboptimal therapeutic group's eGFR decreased in the same period (from 110.4 ± 14 mL/min/1.73 m2 to 94.2 ± 16 mL/min/1.73 m2, p = 0.017). At 10 years, the suboptimal therapeutic group had an increased serum creatinine level (81 ± 14.4 μmol/L vs. 71.5 ± 13 μmol/L, p = 0.038), and a decreased eGFR (94.2 ± 16 mL/min/1.73 m2 vs. 103.3 ± 13 mL/min/1.73 m2p = 0.031) compared to the good adhering group. Significant negative correlation between Phe levels and eGFR (r = -0.41, p = 0.008) was observed.

Conclusion: Long-term suboptimal therapy adherence in PKU patients with high blood Phe levels may lead to deterioration in kidney function.

Introduction: Blood coagulation is associated with glomerulonephritis (GN) pathophysiology. Using whole-blood-based rotational thromboelastometry, we recently reported that the degree of hypercoagulability in pediatric patients with immunoglobulin A nephropathy (IgAN), a GN, might be associated with pathological severity. To further clarify the coagulation status of mesangial proliferative GN (MesPGN), we assessed the platelet thrombus formation (PTF) under high-shear flow using a microchip-based flow chamber system (T-TAS®).

Methods: Thirty-four pediatric patients definitively diagnosed with MesPGN by renal biopsy at Nara Medical University Hospital between 2015 and 2022 were enrolled, and 29 patients (case group; median age, 8.0 years) were assessed. Microchips coated with collagen (PL-chip) were used to assess PTF at high-shear in whole blood. The times to increase by 10 and 30 kPa (T10 and T30) from baseline were calculated and compared with those of the pediatric controls. Changes in the parameters during the treatment course and the relationship between pathological severity and the parameters were evaluated.

Results: T10 and T30 parameters in the PL-chip were significantly shorter, and the area under the curves were greater in the case group than those in the control group (both p < 0.05). Each parameter was enhanced during the 3-week treatment but improved after the end of treatment. No significant relationship was observed between pathological severity and these parameters. Little PTF difference was observed between IgAN and Henoch-Schönlein purpura nephritis.

Conclusions: Pediatric MesPGN increased the potential for PTF under high-shear flow conditions.