Kidney & blood pressure research最新文献

Introduction: Diabetic kidney disease (DKD) is a common cause of chronic kidney disease with around 25-40% of patients with diabetes being affected. The course of DKD is variable, and estimated glomerular filtration rate (eGFR) and albuminuria, the currently used clinical markers, are not able to accurately predict the individual disease trajectory, in particular in early stages of the disease. The aim of this study was to assess the association of urine levels of selected protein biomarkers with the progression of DKD at an early stage of disease.

Methods: We measured 22 protein biomarkers using the Mesoscale Discovery platform in 461 urine samples of the PROVALID cohort, an observational study of patients with type 2 diabetes mellitus followed at the primary health care level for a minimum of 4 years. Odds ratios (ORs) were estimated for the effect of marker values above median on fast progression using unadjusted and adjusted logistic regression models. RNA expression at the single-cell level in kidney biopsy samples obtained from a cohort of young persons with type 2 diabetes mellitus was in addition determined for markers showing significant associations with disease progression.

Results: Increased urinary levels of epidermal growth factor (EGF) were linked to lower odds of fast progression (defined as annual eGFR decline greater than 2.58 mL/min per 1.73 m2) with an OR of 0.60 (95% CI: 0.46, 0.78). The association with outcome was even stronger when adjusting for a set of 14 baseline clinical parameters including age, biological sex, eGFR, body mass index, albuminuria, and HbA1c. Elevated urinary levels of fatty acid-binding protein 3 (FABP3) and vascular cell adhesion molecule 1 (VCAM1) were each significantly associated with fast progression with an OR of 1.44 (95% CI: 1.11, 1.87) and an OR of 1.41 (95% CI: 1.08, 1.83), respectively. Enriched expression of EGF and FABP3 was observed in distal convoluted tubular cells and VCAM1 in parietal epithelial cells at single-cell level from biopsies of patients with early DKD.

Conclusion: In summary, we show that lower urinary levels of EGF and higher urinary levels of FABP3 and VCAM1 are significantly associated with DKD progression in early-stage disease.

Introduction: The aim of this study was to evaluate the predictive value of the serum IgA/C3 ratio and glomerular C3 deposits in kidney biopsy in adult IgA nephropathy.

Methods: The study included 718 adult IgAN patients diagnosed based on kidney biopsy. Patients without corticosteroids or immunosuppressive drugs >1 month were regularly followed up for at least 1 year or until the study endpoint. The optimum serum IgA/C3 ratio was calculated by the AUROC-based cutoff ratio. Proteinuria, creatinine, eGFR, serum IgA, and serum C3 were evaluated at baseline. Kidney biopsy was categorized using the Oxford classification, with a calculation of the MEST-C score. The degree of glomerular C3 staining was semiquantitatively determined (grade 0, no or trace; grade 1, mild; grade 2, moderate; grade 3, marked) by immunofluorescence microscopy. The patients were divided into four groups by the serum IgA/C3 ratio and glomerular C3 staining.

Results: The baseline data suggested that when the serum IgA/C3 ratio was at the same level, patients with a high glomerular C3 staining score (≥2) always had mesangial proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis (group 1 vs. group 2; group 3 vs. group 4). When glomerular C3 staining was at the same level, proteinuria was significantly higher in patients with serum IgA/C3<2.806 (group 1 vs. group 3; group 2 vs. group 4), which was contrary to previous studies that have suggested that the serum level of IgA/C3 was associated with disease severity. Hence, this study set out to investigate the combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome in adult IgA nephropathy. Renal survival analysis indicated that serum IgA/C3 ≥2.806 and glomerular C3 staining ≥2 (group 1) may be correlated with a poorer prognosis, especially in different clinicopathological characteristics of IgAN patients based on the subgroup analysis. Multivariate Cox analysis demonstrated that hypertension, serum creatinine, CKD stage, T1/2 and C3 staining were independent predictive factors of renal survival.

Conclusions: The combination of serum IgA/C3 and C3 staining may contribute to improved optimization of the prognostic model in IgAN patients, especially patients with different sexes and degrees of disease. However, further study is required for validation in the future.

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors target SGLT2 in renal proximal tubules and promote glycosuria in type 2 diabetes mellitus in humans and animal models, resulting in reduced blood glucose levels. Although clinical trials have shown that SGLT2 inhibitors attenuate the progression of chronic kidney disease, there have been concerns regarding SGLT2-induced acute kidney injury. In this study, we investigated the effect of SGLT2 inhibitors on adriamycin-induced kidney injury in mice.

Methods: Seven-week-old balb/c mice were injected with adriamycin 11.5 mg/kg via the tail vein. Additionally, dapagliflozin was administered via gavage for 2 weeks. The mice were divided into five groups: vehicle, dapagliflozin 3 mg/kg, adriamycin, adriamycin plus dapagliflozin 1 mg/kg, and adriamycin plus dapagliflozin 3 mg/kg.

Results: Adriamycin injection reduced the body weight and food and water intakes. Dapagliflozin also decreased the body weight and food and water intakes. Fasting blood glucose and urine volume were not altered by either adriamycin or dapagliflozin. Once adriamycin-induced kidney injury had developed, there were no differences in systolic blood pressure among the groups. Dapagliflozin did not alleviate proteinuria in adriamycin-induced kidney injury. Adriamycin induced significant glomerular and interstitial injury, but dapagliflozin did not attenuate these changes in renal injury. Interestingly, SGLT2 expressions were different between the cortex and medulla of kidneys by dapagliflozin treatment. Dapagliflozin increased SGLT2 expression in medulla, not in cortex.

Conclusion: Dapagliflozin had no effect on proteinuria or inflammatory changes such as glomerular and tubular damages in adriamycin-induced kidney injury. Our study suggests that dapagliflozin does not protect against adriamycin-induced kidney injury. More experimental studies regarding the effects of SGLT2 inhibitors on various kidney diseases are needed to clarify the underlying mechanisms.

Introduction: High serum phosphorus level has been reported to be a risk factor for disease progression in patients with chronic kidney disease, whereas, its role in IgA nephropathy (IgAN) still remains uncertain. This study aimed to investigate the association between serum phosphorus and progression of IgAN.

Methods: A total of 247 patients diagnosed with IgAN from 2016.11 to 2019.12 at the First Affiliated Hospital of Xi'an Jiaotong University were retrospectively enrolled in this study. The association between serum phosphorus and kidney disease progression events, defined as 30% estimated glomerular filtration rate (eGFR) decline or kidney failure, was evaluated using Cox models.

Results: Serum phosphorus was an independent risk factor for poor renal outcome after adjusting for age, gender, urine protein, MAP, eGFR, hemoglobin, Oxford S and T scores (HR, 2.586; 95% CI, 1.238-5.400, p = 0.011). The addition of serum phosphorus to the reference model containing clinical and pathological variables significantly improved the risk prediction of IgAN progression (C statistic, 0.836; 95% CI, 0.783-0.889) as compared with the reference model (C statistic, 0.821; 95% CI, 0.756-0.886). The ability of serum phosphorus level to predict progression was much stronger in IgAN patients without use of immunosuppression (HR 5.173; 95% CI, 1.791-14.944; p = 0.002).

Conclusion: Higher serum phosphorus levels were independently associated with kidney disease progression in patients with IgAN, especially in those without immunosuppression. The addition of serum phosphorus to clinical and pathological data at the time of biopsy significantly improved risk prediction of IgAN progression.

Introduction: Opioid analgesics are often used to manage moderate to severe pain. A significant proportion of patients taking opioids have compromised kidney function. This systematic review aimed to examine the available evidence on the safety and analgesic effect of opioid use in adults with kidney disease.

Methods: We searched eight electronic databases from inception to January 26, 2023. Published original research articles in English reporting on opioid use and pharmacokinetic data among adults with reduced renal function were included. Article screening, data extraction, and quality assessment were conducted by at least two investigators independently. This review was registered prospectively on PROSPERO (ID: CRD42020159091).

Results: There were 32 observational studies included, 14 of which reported on morphine use, three involved fentanyl use, two involved hydromorphone use, and 13 articles reported on other opioids including codeine, dihydrocodeine, and buprenorphine.

Conclusion: There is limited and low-quality evidence to inform the safety and analgesic effect of opioid use in reduced renal function. Morphine remains the opioid for which there is the most evidence available on safety and analgesic effect in the context of renal disease. Greater caution and consideration of potential risks and benefits should be applied when using other opioids. Further high-quality studies examining clinical outcomes associated with the use of different opioids and opioid doses in renal disease are warranted.

Introduction: The early diagnosis of kidney injury in type 2 diabetes (T2DM) is important to prevent the long-term damaging effects of kidney loss and is decisive for patient outcomes. While SIRT2 is implicated in diabetes pathogenesis, its correlation with diabetic nephropathy remains unexplored. This study was designed to evaluate the association of urine SIRT2 levels with diabetic kidney injury, as well as potential underlying mechanisms.

Methods: In T2DM patients, db/db mice, and high glucose plus palmitic acid treated HK2 cell models, ELISA, Immunoturbidimetry, Immunohistochemistry, Western blot, and Quantitative real-time polymerase chain reaction were used to detect SIRT2 levels and kidney damage. According to urinary albumin/creatinine ratio (UACR), 163 T2DM patients were divided into three groups. Spearman correlation analysis was used to investigate the relationship between urinary sirtuin2/creatinine ratio (USCR) and biomarkers of kidney injury. The influencing factors of albuminuria in T2DM patients were analyzed by logistic regression model.

Results: In our findings, the Macro group exhibited the highest USCR levels as UACR increased. There was a positive association between USCR and UACR, α1-microglobulin/creatinine ratio (UαCR), β2-microglobulin/creatinine ratio (UβCR), and retinol-binding protein/creatinine ratio (URCR), with a negative correlation observed with eGFR. Logistic ordered multiclassification regression analysis, adjusting for confounding variables, confirmed that USCR remained a significant risk factor for the severity of albuminuria in T2DM patients. In the db/db mice kidney SIRT2 protein level increased significantly. Increased SIRT2 protein levels were also observed in renal tubular epithelial cells treated with high glucose plus palmitic acid. Moreover, SIRT2 promotes the expression of proinflammatory factors TNF-α and IL-6 by modulating the phosphorylation of p38 MAPK and p-JNK in renal tubular cells induced by high glucose and palmitic acid.

Conclusion: Urinary SIRT2 is closely related to eGFR, renal tubule injury, and urinary albumin excretion in T2DM patients, which is expected to be an important indicator to comprehensively reflect renal injury.

Introduction: The diagnosis of Fabry disease (FD) with genetic variants of unknown significance (VUSs) is relatively difficult. We explored patients with novel VUS variants and concomitant immunoglobulin A nephropathy (IgAN) to improve the understanding of VUS.

Methods: The study retrospectively investigated patients with genetically confirmed FD. Probands with VUS were selected from the database of FD patients who underwent genetic analysis. Demographic, clinicopathological, and laboratory data from probands and family members were collected and analyzed.

Results: Fourteen probands and their family members were included in the study. The probands were divided into group 1 (patients with VUS, n = 5) and group 2 (patients with pathologic/likely pathologic variants, n = 9). The group 1 included 2 missense mutations and 1 deletion mutation, while the group 2 included 6 missense mutations and 2 deletion mutations. There were no significant differences in gender, age, serum creatinine, eGFR, and proteinuria between the two groups. IgA deposition with myeloid bodies was found in all VUS patients. The cardiac involvement in group 2 was more severe than that in group 1. Seven families performed the pedigree analysis, and after the comprehensive evaluation, two GLA variants (c.479C>A, p.Ala160Asp; c.1032-1058 del, p.Ser345_Met353del) were upgraded from VUS to the likely pathogenic.

Conclusion: The clinical manifestations of FD are heterogeneous. FD often coexists with nephrotic disorders, such as IgAN and MCD. Comprehensive evaluation, especially tissue-specific biopsy, is necessary for patients with GLA-VUSs. Two GLA variants (c.479C>A, p.Ala160Asp; c.1032-1058 del, p.Ser345_Met353del) were upgraded from VUS to the likely pathogenic after the comprehensive evaluation.

Introduction: Nephrotic syndrome may persist despite end-stage kidney disease and result in dyslipidaemia, thrombosis and a significantly increased cardiovascular risk. Treatment of refractory nephrotic syndrome includes surgical bilateral nephrectomy, renal artery embolization and pharmacologic nephrectomy.

Case presentation: We present a case of a haemodialysis patient with refractory nephrotic syndrome who underwent pharmacologic nephrectomy. The procedure decreased the patient's cardiovascular risk and enabled the patient to become a candidate for kidney transplantation.

Conclusion: In certain situations residual renal function may be harmful. In such instances, nephrectomy should be considered. Pharmacologic nephrectomy using nephrotoxic drugs is a non-invasive approach with least potential complications.

Introduction: Physical inactivity is common in patients with chronic kidney disease (CKD) and is an important modifiable risk factor for mortality, morbidity, and reduced quality of life. The present single-centre pilot study evaluated the possibility of performing structured physical exercise using a specific walking model, Fitwalking, in a population of patients with CKD and, according to the American College of Rheumatology guidelines, also in a population with immuno-rheumatological disease.

Methods: Patients were recruited from nephrology, haemodialysis, peritoneal dialysis, transplantation, and immuno-rheumatology outpatient clinics. After general and functional clinical evaluation and exercise prescription at the Department of Sports Medicine, we performed scientifically proven tests on CKD (6-min walk test and sit-to-stand test), before and after the Fitwalking technique training course, and again after 6 and 12 months, evaluated its effectiveness and identify any critical issues.

Results: We enrolled 80 patients (41 males, 51.2%), with a mean age of 53 ± 12 years; the clinical data showed statistically significant improvements in systolic, average, and differential blood pressure, average speed, and physical strength. Participants also adapted to muscle fatigue, experienced a reduction in BMI with stable lean mass and reduced fat mass, and reported improved perceptions of physical and mental health, and quality of life.

Conclusion: All enrolled patients successfully completed the process. A specific prescription was used that provided health education and allowed for the implementation of structured physical activity that could be performed safely and independently even after the training period. The activity was sustainable thanks to the training of in-house medical and nursing staff, demonstrating that it is possible to overcome this type of barrier to physical activity in CKD and in immuno-rheumatological patients.

Introduction: Acute kidney injury (AKI) is a prevalent renal disorder. The occurrence of AKI may promote the formation of renal calcium oxalate stones by exerting continuous effects on renal tubular epithelial cells (TECs). We aimed to delineate the molecular interplay between AKI and nephrolithiasis.

Methods: A mild (20 min) and severe (30 min) renal ischemia-reperfusion injury model was established in mice. Seven days after injury, calcium oxalate stones were induced using glyoxylate (Gly) to evaluate the impact of AKI on the formation of kidney stones. Transcriptome sequencing was performed on TECs to elucidate the relationship between AKI severity and kidney stones. Key transcription factors (TFs) regulating differential gene transcription levels were identified using motif analysis, and pioglitazone, ginkgetin, and fludarabine were used for targeted therapy to validate key TFs as potential targets for kidney stone treatment.

Results: Severe AKI led to increased deposition of calcium oxalate crystals in renal, impaired kidney function, and upregulation of kidney stone-related gene expression. In contrast, mild AKI was associated with decreased crystal deposition, preserved kidney function, and downregulation of similar gene expression. Transcriptomic analysis revealed that genes associated with inflammation and cell adhesion pathways were significantly upregulated after severe AKI, while genes related to energy metabolism pathways were significantly upregulated after mild AKI. An integrative bioinformatic analysis uncovered a TF regulatory network within TECs, pinpointing that PKNOX1 was involved in the upregulation of inflammation-related genes after severe AKI, and inhibiting PKNOX1 function with pioglitazone could simultaneously reduce the increase of calcium oxalate crystals after severe AKI in kidney. On the other hand, motif analysis also revealed the protective role of STAT1 in the kidneys after mild AKI, enhancing the function of STAT1 with ginkgetin could reduce kidney stone formation, while the specific inhibitor of STAT1, fludarabine, could eliminate the therapeutic effects of mild AKI on kidney stones.

Conclusion: Inadequate repair of TECs after severe AKI increases the risk of kidney stone formation, with the upregulation of inflammation-related genes regulated by PKNOX1 playing a role in this process. Inhibiting PKNOX1 function can reduce kidney stone formation. Conversely, after mild AKI, effective cell repair through upregulation of STAT1 expression can protect TEC function and reduce stone formation, and activating STAT1 function can also achieve the goal of treating kidney stones.