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BACKGROUND/AIM: Angiotensinogen (AGT), a precursor of angiotensin II (AngII), contributes to regulating (patho)physiological conditions, including blood pressure changes, inflammation, and kidney fibrosis. However, the precise role of tissue-specific AGT in kidney fibrosis independent of blood pressure remains to be fully understood. This study investigated the source of intrarenal AGT and its role in kidney injury and fibrosis during obstructive nephropathy. MATERIALS AND METHODS: Proximal tubule- (PT, major source secreting AGT in the kidney; PKO) or liver- (major source of circulating AGT; LKO) AGT knockout (KO) mice were subjected to unilateral ureteral obstruction (UUO), a blood pressure-independent fibrosis model. RESULTS: UUO increased AGT mRNA and protein levels in the kidneys. PKO decreased AGT mRNA, but LKO enhanced it in UUO kidneys compared with the control. In contrast, the intrarenal protein levels of AGT increased in PKO, but not in LKO in UUO kidneys, indicating that the liver is a major source of intrarenal AGT protein. Expression of megalin, a PT receptor involved in the uptake of circulating AGT, was down-regulated in UUO kidneys and was independent of PKO or LKO. However, none of these changes prevented UUO-induced tubular injury and kidney fibrosis. CONCLUSION: Hepatic and proximal tubule AGT play distinct roles in contributing to intrarenal AGT levels during UUO, and their genetic inhibitions fail to prevent kidney injury and fibrosis, suggesting a highly complicated signaling pathway of the renin-angiotensin system and an associated compensatory mechanism in obstructive nephropathy.
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Angiotensinógeno , Modelos Animales de Enfermedad , Fibrosis , Riñón , Ratones Noqueados , Obstrucción Ureteral , Animales , Ratones , Angiotensinógeno/metabolismo , Angiotensinógeno/genética , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/patología , Enfermedades Renales/genética , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Hígado/metabolismo , Hígado/patología , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/genética , Obstrucción Ureteral/patologíaRESUMEN
INTRODUCTION: Inflammatory and immunological responses are reported involved in the pathogenesis and progression of obstructive nephropathy (ON). This study was designed to investigate the characteristics of peripheral immunity in patients with upper urinary tract urolithiasis and analyze the underlying associations with renal function. METHODS: Patients with unilateral upper urinary tract urolithiasis meeting the operation indications were prospectively enrolled. Preoperative circulating immune cells and inflammatory cytokines were detected in our clinical laboratory, and the indicators of renal function and calculi related parameters were particularly recorded. Patients were sectionalized into subgroups on the basis of the lesion of calculi. Characteristics of peripheral immunity in each subgroup were investigated by statistical approaches, and the underlying correlations with the degree of hydronephrosis (HN) and renal function were discussed in corresponding group. RESULTS: Patients with ureteral calculi presented severer HN compared with renal calculi, especial middle ureteral calculi, acting as the chief culprit of ON, exhibiting the highest serum creatine and blood urea nitrogen, most impaired estimated glomerular filtration rate, and severest HN. In addition, serum interleukin-8 (IL-8) and IL-6 were demonstrated presenting statistical differences between ureteral calculi and renal calculi patients, exhibiting underlying values in comprehending ON. However, circulating immune cells were demonstrated no obvious differences among groups. CONCLUSIONS: Circulating inflammatory cytokines, referred in particular to serum IL-8 and IL-6 were partially associated with kidney injury in patients with upper urinary tract urolithiasis. But the specific influences and mechanisms between them needed to be investigated furthermore.
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Cálculos Ureterales , Humanos , Masculino , Femenino , Persona de Mediana Edad , Cálculos Ureterales/inmunología , Cálculos Ureterales/complicaciones , Adulto , Estudios Prospectivos , Cálculos Renales/inmunología , Riñón/inmunología , Riñón/fisiopatología , Hidronefrosis/sangre , Hidronefrosis/etiología , Hidronefrosis/inmunología , Urolitiasis/inmunología , Citocinas/sangre , Anciano , Estudios TransversalesRESUMEN
OBJECTIVE: The purpose of this study was to investigate the role and possible mechanism of lncRNA XIST in renal fibrosis and to provide potential endogenous targets for renal fibrosis in obstructive nephropathy (ON). METHODS: The study included 50 cases of ON with renal fibrosis (samples taken from patients undergoing nephrectomy due to ON) and 50 cases of normal renal tissue (samples taken from patients undergoing total or partial nephrectomy due to accidental injury, congenital malformations, and benign tumors). Treatment of human proximal renal tubular epithelium (HK-2) cells with TGF-ß1 simulated renal fibrosis in vitro. Cell viability and proliferation were measured by CCK-8 and EdU, and cell migration was measured by transwell. XIST, miR-124-3p, ITGB1, and epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, α-SMA, and fibronectin) were detected by PCR and immunoblot. The targeting relationship between miR-124-3p and XIST or ITGB1 was verified by starBase and dual luciferase reporter gene experiments. In addition, The left ureter was ligated in mice as a model of unilateral ureteral obstruction (UUO), and the renal histopathology was observed by HE staining and Masson staining. RESULTS: ON patients with renal fibrosis had elevated XIST and ITGB1 levels and reduced miR-124-3p levels. The administration of TGF-ß1 exhibited a dose-dependent promotion of HK-2 cell viability, proliferation, migration, and EMT. Conversely, depleting XIST or enhancing miR-124-3p hindered HK-2 cell viability, proliferation, migration, and EMT in TGF-ß1-damaged HK-2 cells HK-2 cells. XIST functioned as a miR-124-3p sponge. Additionally, miR-124-3p negatively regulated ITGB1 expression. Elevating ITGB1 weakened the impact of XIST depletion on TGF-ß1-damaged HK-2 cells. Down-regulating XIST improved renal fibrosis in UUO mice. CONCLUSION: XIST promotes renal fibrosis in ON by elevating miR-124-3p and reducing ITGB1 expressions.
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Transición Epitelial-Mesenquimal , Fibrosis , Enfermedades Renales , MicroARNs , ARN Largo no Codificante , ARN Largo no Codificante/genética , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Fibrosis/genética , Fibrosis/patología , Fibrosis/metabolismo , Animales , Ratones , Enfermedades Renales/genética , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Transición Epitelial-Mesenquimal/genética , Integrina beta1/metabolismo , Integrina beta1/genética , Proliferación Celular , Masculino , Movimiento Celular/genética , Riñón/patología , Riñón/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Línea Celular , Femenino , Obstrucción Ureteral/patología , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/genéticaRESUMEN
Renal fibrosis is among the major factors contributing to the development of chronic kidney disease. In this regard, although N6-methyladenosine (m6A) modification and micro-RNAs (miRNAs) have been established to play key roles in diverse physiological processes and disease/disorder development, further research is required to identify the probable mechanisms and processes associated with their involvement in renal fibrosis. In this study, we show that transforming growth factor ß1 (TGF-ß1)-induced human proximal tubule epithelial cells (HK2) are characterized by dose-dependently higher methyltransferase-like 3 (METTL3) expression. Furthermore, METTL3 was found to enhance pri-miR-199a-3p maturation and miR-199a-3p expression in an m6A-dependent manner, whereas miR-199a-3p sponges prostate apoptotic response 4 (Par4), thereby regulating its expression. Collectively, our findings in this study indicate that the METTL3/miR-199a-3p/Par4 axis plays a key role in the development of obstructive nephrogenic fibrosis.
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Fibrosis , Metiltransferasas , MicroARNs , Factor de Crecimiento Transformador beta1 , Metiltransferasas/genética , Metiltransferasas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Línea Celular , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Enfermedades Renales/genética , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/metabolismo , Animales , Regulación de la Expresión Génica , Transducción de Señal/genética , Adenosina/análogos & derivados , Adenosina/metabolismoRESUMEN
Background and objective Chronic kidney disease (CKD) poses a significant global public health challenge, especially among the Asian population who experience higher prevalence and more rapid disease progression. This study aimed to compare the epidemiology and risk factors associated with CKD between rural and urban residents in Peshawar, Pakistan. Materials and methods A cross-sectional study involving adult patients with CKD was conducted at a public tertiary care hospital in Peshawar between July 2023 and January 2024. To collect data, a tool was developed based on existing literature. CKD was defined as follows: a low estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m2, albuminuria (urine albumin-creatinine ratio >3 mg/mmol), or a combination of both low eGFR and albuminuria. The prevalence of moderate to severe CKD, adjusted for place of residence, was calculated. Statistical analysis was performed using SPSS Statistics V. 26 (IBM Corp., Armonk, NY). Results Among the study sample, 114 (41.45%) patients hailed from rural areas while 161 (58.55%) resided in urban areas. Urban patients had a higher prevalence of albuminuria levels below 30 mg/g than rural patients (83.2% vs. 76.3%, p=0.00). Additionally, the mean eGFR was slightly higher among rural residents. Rural patients had a higher prevalence of hypertension, and there was a noticeable disparity in the occurrence of kidney stones, with rural residents experiencing a greater incidence. Patients living in urban areas showed a higher level of understanding of risk factors and reported taking preventive measures for CKD. Factors associated with moderate to severe CKD included living in urban areas and having a medical history of diabetes and hypertension (p=0.00). No significant association was observed between behavioral factors and the severity of CKD. Conclusions Urban residents exhibited higher rates of CKD and albuminuria and had a greater awareness of CKD risk factors. In contrast, rural areas had a slightly higher mean eGFR and greater prevalence of hypertension and kidney stones. Diabetes and hypertension were key predictors of moderate to severe CKD.
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BACKGROUND: Accurate estimation of the glomerular filtration rate (GFR) is clinically crucial for determining the status of obstruction, developing treatment strategies, and predicting prognosis in obstructive nephropathy (ON). We aimed to develop a deep learning-based system, named UroAngel, for non-invasive and convenient prediction of single-kidney function level. METHODS: We retrospectively collected computed tomography urography (CTU) images and emission computed tomography diagnostic reports of 520 ON patients. A 3D U-Net model was used to segment the renal parenchyma, and a logistic regression multi-classification model was used to predict renal function level. We compared the predictive performance of UroAngel with the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, and two expert radiologists in an additional 40 ON patients to validate clinical effectiveness. RESULTS: UroAngel based on 3D U-Net convolutional neural network could segment the renal cortex accurately, with a Dice similarity coefficient of 0.861. Using the segmented renal cortex to predict renal function stage had high performance with an accuracy of 0.918, outperforming MDRD and CKD-EPI and two radiologists. CONCLUSIONS: We proposed an automated 3D U-Net-based analysis system for direct prediction of single-kidney function stage from CTU images. UroAngel could accurately predict single-kidney function in ON patients, providing a novel, reliable, convenient, and non-invasive method.
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Aprendizaje Profundo , Insuficiencia Renal Crónica , Riñón Único , Humanos , Estudios Retrospectivos , Riñón/diagnóstico por imagen , Insuficiencia Renal Crónica/diagnóstico , Tasa de Filtración Glomerular , Tomografía , CreatininaRESUMEN
INTRODUCTION: Obstructive uropathy encompasses various urinary tract obstructions, leading to changes in urine flow, kidney pressure, and impaired kidney function. Predicting renal recovery from obstructive uropathy, can be challenging and necessitates treatment, as in percutaneous nephrostomy (PNS) drainage. The choice of drainage method depends on patient-specific factors and local expertise. According to the data for the Republic of North Macedonia, in the register of the European Renal Association, in the last few years, there has been an increase in the percentage of patients with obstructive nephropathy from 7.6% to 8.9% who end up on a chronic hemodialysis program. Prompt relief from urinary tract obstruction is essential to preserve renal function and prevent complications. The aim of this study is to present our initial data analysis of recent experience in the use of nephrostomies as a method for temporary or long-term resolution of obstructive nephropathy, in terms of safety and success in preserving kidney function and reducing the number of patients on hemodialysis. MATERIALS AND METHODS: This study analyzed the medical records of 24 patients with obstructive uropathy who underwent PNS placement. Data were collected for the type and degree of obstruction from the ultrasonographic examination. A pig tail nephrostomy was used, with a dilator, guided under ultrasound and controlled with contrast and fluoroscope. Obstructive nephropathy was defined as an elevation of the serum creatinine > 109 µmol/L, before the intervention. Glomerular filtration rate (GFR) was calculated according to the formula CKD epi in ml/min. Each placement of the PNS was considered as an individual procedure and the data of 38 placed nephrostomies were analyzed. We compared the laboratory analyses from the day before (D0) PNS placement and on the seventh day (D7) after PNS placement. The reduction of values for red blood cells (RBC) and hemoglobin (Hb) baseline values from D0 to D7 and the need for transfusion after the procedure were defined as a complication-bleeding. The increase in total counts of the white blood cells (WBC) and C-reactive protein (CRP) from the baseline values from D0 to D7 were defined as a complication-infection. Standard statistical methods were used for data processing. RESULTS: Most patients, 17 (70%), had malignant disease as the cause of obstruction. Unilateral obstruction was more common, detected in 24 (63%) of procedures, with a high degree of hydronephrosis. Obstructive nephropathy, marked by elevated serum creatinine, was observed in 23 (60%) cases before PNS placement. Complications included bleeding and infection but did not result in any fatalities. When comparing the laboratory analysis before PNS placement (D0) and seven days later (D7), a statistically significant decrease in serum creatinine (225±161 vs. 162±145, p=0.005) and an increase in GFR (47±39 vs.59±34, p= 0.005) were observed. CONCLUSION: Percutaneous nephrostomy is a safe and effective treatment option for urinary tract obstruction, especially in patients with malignancies. Continuous monitoring is essential to assess long-term complications and the longevity of PNS functionality. This procedure offers a significant benefit in preserving renal function and minimizing the need for hemodialysis in these patients.
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Neoplasias , Nefrostomía Percutánea , Urología , Humanos , Nefrostomía Percutánea/efectos adversos , Nefrostomía Percutánea/métodos , Creatinina , Universidades , RiñónRESUMEN
Lower urinary tract foreign bodies are often reported but the underlying causes remain intriguing, ranging from unconventional practices to medical interventions. This condition predominantly affects young males and presentations are varied from asymptomatic, lower urinary tract symptoms to acute obstructive renal failure. We report a case of a 48-year-old male presented with lower urinary tract symptoms and obstructive renal failure. Imaging revealed multiple foreign bodies in the pelvic cavity, suggestive of vesical, and urethral lithiasis. Urethrocystoscopy removed an 8-cm needle with rubber band and a 10-cm encrusted cable, forming a urethral stone. Vesicolithotomy removed a 5 × 3 cm bladder stone with a SIM card inserter as its core. The patient's condition improved after surgery. Notably, the patient's history prompted a psychiatric evaluation, leading to the diagnosis of and treatment for an adjustment disorder. While endourology procedure is effective in most cases, some cases necessitate open surgery. Identification and treatment of underlying psychiatric disorders is needed to for long term care.
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Introduction Acute kidney injury (AKI) is an abrupt reduction in kidney function that causes nitrogenous waste and other waste products to be retained. Methods This cross-sectional study was conducted from February 2015 to January 2016. The study received approval from the Independent Ethics Committee, which included patients over 60 with AKI. The study duration was 12 consecutive months to ascertain the etiology, severity, and hospital outcomes of AKI. Results The common etiologies of AKI included drug-induced (25%), age-related (21.67%), cardiac (13.33%), respiratory (20%), tropical (15%), and pancreatitis (15%) cases. Another predominant etiology observed was obstructive nephropathy (55%), with the highest (37.5%) mortality rate. The distribution of patients based on KDIGO criteria showed no significant difference in mortality percentages among classes (p=0.177). Conservative management without renal replacement therapy was the most common approach to treat AKI, with a 39% mortality rate. Conclusion Among different causes of AKI in the geriatric age group, drug-induced AKI, and obstructive nephropathy were predominantly associated with hospital mortality.
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OBJECTIVES: Erythropoietin (EPO) exerts tissue-protective effects on various organs including the kidney. However, the effects of EPO on established renal fibrosis remain unclear. In this study, we aimed to examine the therapeutic potential of EPO against established renal fibrosis. METHODS: Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) and the mice were treated with recombinant human EPO (rhEPO) daily during 7 and 13 days after UUO. The degrees of renal fibrosis, myofibroblast accumulation, and macrophage infiltration; the mRNA expression levels of transforming growth factor (TGF)-ß1 and α1(I) collagen; and the protein levels of Kelch-like ECH-associated protein 1 (Keap1) and nuclear NF-E2-related factor 2 (Nrf2) in the kidneys were assessed on day 14 after UUO. RESULTS: Treatment with rhEPO significantly decreased fibrosis, myofibroblast accumulation, and α1(I) collagen mRNA expression, but it did not significantly affect TGF-ß1 mRNA expression. Although treatment with rhEPO did not significantly affect the total number of interstitial macrophages, it significantly decreased the number of CD86-positive cells (M1 macrophages), while significantly increased the number of CD206-positive cells (M2 macrophages) in the interstitium. Treatment with rhEPO did not affect the Keap1/Nrf2 protein level or the peripheral blood hematocrit value. CONCLUSIONS: These results indicate for the first time that EPO exerts antifibrotic effects against the evolution of established renal fibrosis, possibly by influencing the polarization of infiltrating macrophages.
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Modelos Animales de Enfermedad , Eritropoyetina , Fibrosis , Riñón , Factor de Crecimiento Transformador beta1 , Obstrucción Ureteral , Animales , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/patología , Eritropoyetina/farmacología , Eritropoyetina/uso terapéutico , Ratones , Masculino , Factor de Crecimiento Transformador beta1/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/prevención & control , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Retraso del TratamientoRESUMEN
Background & Objectives: Percutaneous nephrostomy (PN) for malignant ureteric obstruction (MUO) is increasingly accessible with high success rates. However, it is not without associated risks and morbidity, impacting quality of life, while not improving overall survival. In two UK hospitals, we investigated the outcomes of undergoing PN for MUO, to inform future patient counselling and selection for this intervention. Methods: A retrospective audit of electronic records identified patients that received PN for bladder, and prostate cancer (PCa) between January 2015 and December 2018. Hospital 1 had a 24-h nephrostomy service, while Hospital 2 had a limited service; Group A: recurrent or treatment-resistant PCa, Group B: primary PCa, Group C: Bladder cancer. Results: A total of 261 patients (Hospital 1 = 186, Hospital 2 = 75), had PN insertion. Seventy-eight had prostate or bladder cancer. Group A n = 30, Group B n = 12, Group C n = 36. Median age = 79 [interquartile range (IQR) = 72-86]. Following PN insertion, 12-month mortality was significantly greater in Hospital 1 at 82%, versus 52% in Hospital 2 (p = 0.015). Median survival: Group A: 177 days (IQR = 80-266), Group B: 209 days (IQR = 77-352), Group C: 145 days (IQR = 97-362). There was no significant difference in same-admission mortality, although group A had the greatest same-admission mortality at 17%. A total of 69% of all patients received bilateral nephrostomies. Patients with bilateral versus unilateral PN had no difference in mortality or nadir creatinine. Conclusion: Most patients with malignant obstruction secondary to prostate or bladder cancer lived less than 12 months after PN insertion. When offering PN, careful consideration of disease prognosis should be made, and frank discussion of the implications of a life-long nephrostomy with patients and relatives.
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Introduction: The unilateral ureteral obstruction (UUO) model is the most extensively used model to investigate chronic renal fibrosis. Macrophages play a critical role in the UUO model. We aimed to analyze the phenotype of macrophages from different sources activated in vitro and explore the role of M1 macrophages from various sources in UUO. Material and methods: C57BL/6 mice were randomly allocated to five different groups (n = 5 per group): the sham-operated control group, PBS-treated (UUO + PBS) group, bone marrow-derived M1 macrophage-treated (UUO + BM1) group, peritoneal M1 macrophage-treated (UUO + PM1) group, and splenic M1 macrophage-treated (UUO + SPM1) group. After M1 macrophages were injected into the tail vein of UUO-treated mice, renal fibrosis indexes were determined using HE, Masson staining, and α-SMA. Results: Compared to those in the UUO + PBS group, the pathological changes were much more severe in the UUO + BM1, UUO + PM1, and UUO + SPM1 groups. Compared to that in the UUO + PBS group, UUO + BM1 group, and UUO + SPM1 group, the collagen area in the UUO + PM1 group was higher at post-UUO day 5 (p < 0.01). The expression of α-SMA in the UUO + PM1 group was higher than that in the UUO + PBS group, UUO + BM1 group, and UUO + SPM1group (p < 0.001). Conclusions: The M1 macrophages cultured in vitro were reinjected into mice and aggravated kidney injury and fibrosis. Compared with BM1 and SPM1, PM1 demonstrated a stronger effect on inducing renal injury and fibrosis.
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Renal fibrosis is a common result for various chronic kidney diseases developing to the end stage. It is a pathological process characterized by the destruction of normal kidney structure and the subsequent replacement with fibrous tissue, which primarily involves fibroblast proliferation and extracellular matrix deposition. Obstruction is a common cause of renal fibrosis, and obstructive renal fibrosis is a common disease in urology. Obstructive renal fibrosis, characterized by its insidious onset, is the result of a complex interplay of multiple factors. These factors encompass renal tubular epithelial cell injury, the presence of a hypoxic microenvironment in affected kidney tissue, inflammatory cell infiltration, release of inflammatory mediators, and the release of renal fibrosis growth factors, among others. This paper reviews the research progress on the mechanism and treatment of renal interstitial fibrosis.
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Adenine phosphoribosyl transferase (APRT) deficiency is an autosomal recessive disorder and a rare cause of urolithiasis due to mutations in APRT (OMIM #102600). APRT deficiency results in increased urinary excretion of 2,8-dihydroxyadenine (DHA) which can cause urolithiasis and kidney failure. However, with prompt diagnosis, patients with APRT deficiency can be treated with xanthine oxidoreductase inhibitors which decrease urinary DHA excretion and improve outcomes. We report a pair of siblings, an 11-year-old brother and his 14-year-old sister with compound heterozygous variants c.270del (p.Lys91Serfs*46) and c.484_486del (p.Leu162del) in APRT with variable clinical presentation of APRT deficiency. The brother presented at 17 months of age with urolithiasis and severe acute kidney injury. His elder sister remained well and asymptomatic with normal kidney function and did not develop renal calculi. Brownish disk or sphere-like crystals with both concentric and radial markings were reported on urine microscopy in the sister on screening. The sister's diagnosis was confirmed with further laboratory evidence of absent red cell lysate APRT activity with corresponding elevated levels of urinary DHA. In conclusion, we identified a novel mutation in the APRT gene in a pair of siblings with greater phenotypic severity in the male.
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Microscopía , Urolitiasis , Niño , Humanos , Masculino , Adenina/uso terapéutico , Adenina/orina , Adenina Fosforribosiltransferasa/genética , Adenina Fosforribosiltransferasa/orina , Urinálisis , Urolitiasis/diagnóstico , Urolitiasis/genéticaRESUMEN
Objective: To determine the factors associated with renal function recovery in individuals with kidney failure due to obstruction in the urinary tract. METHODS: The prospective, descriptive study was conducted July 2020 to August 2021 at the Department of Urology, Sindh Institute of Urology and Transplantation, Karachi, and comprised adult patients of either gender who had renal failure secondary to obstructive urinary tract. Baseline data regarding patients' variables, including age, gender, duration of symptoms (<25 days or >25 days), haemoglobin (<9.85g/dl or >9.85g/dl), serum creatinine and renal cortical thickness (<16.5mm or >16.5 mm), was noted on a proforma. The variables were stratified to assess impact on renal recovery. Data was analysed using SPSS 23. RESULTS: Of the 126 patients, 43(34.13%) were males and 83(65.87%) were females. The overall mean age was 44.13±14.18 years. Renal recovery occurred in 67(78.8%) patients having duration of symptoms ≤25 days, and in 13(31.7%) patients with duration of symptoms >25 days (p<0.001). Renal recovery occurred in 41(58.6%) patients having haemoglobin ≤9.85g/dL and in 39(69.6%) patients having haemoglobin >9.85g/dL (p=0.2). Renal recovery occurred in 26(37.7%) patients with parenchymal thickness ≤16.5mm and in 54(94.7%) patients with renal cortical thickness >16.5mm (p<0.001). Conclusion: Symptom duration ≤25 days, and renal parenchymal thickness >16.5mm were found to be predictive factors of good recovery in renal failure cases secondary to obstructive uropathy.
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Insuficiencia Renal , Obstrucción Ureteral , Enfermedades Uretrales , Adulto , Masculino , Femenino , Humanos , Persona de Mediana Edad , Recién Nacido , Estudios Prospectivos , Recuperación de la Función , Riñón , Insuficiencia Renal/complicaciones , Obstrucción Ureteral/complicacionesRESUMEN
AIM: Ureteral obstruction leads to significant changes in kidney renin expression. It is unclear whether those changes are responsible for the progression of kidney damage, repair, or regeneration. In the current study, we aimed to elucidate the contribution of renin-producing cells (RPCs) and the cells of the renin lineage (CoRL) towards kidney damage and regeneration using a model of partial and reversible unilateral ureteral obstruction (pUUO) in neonatal mice. METHODS: Renin cells are progenitors for other renal cell types collectively called CoRL. We labeled the CoRL with green fluorescent protein (GFP) using genetic approaches. We performed lineage tracing to analyze the changes in the distribution of CoRL during and after the release of obstruction. We also ablated the RPCs and CoRL by cell-specific expression of Diphtheria Toxin Sub-unit A (DTA). Finally, we evaluated the kidney damage and regeneration during and after the release of obstruction in the absence of CoRL. RESULTS: In the obstructed kidneys, there was a 163% increase in the renin-positive area and a remarkable increase in the distribution of GFP+ CoRL. Relief of obstruction abrogated these changes. In addition, DTA-expressing animals did not respond to pUUO with increased RPCs and CoRL. Moreover, reduction in CoRL significantly compromised the kidney's ability to recover from the damage after the release of obstruction. CONCLUSIONS: CoRL play a role in the regeneration of the kidneys post-relief of obstruction.
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Riñón , Obstrucción Ureteral , Ratones , Animales , Riñón/metabolismo , Renina/metabolismo , Animales Recién Nacidos , Obstrucción Ureteral/metabolismo , Ratones Transgénicos , RegeneraciónRESUMEN
OBJECTIVE: Glomerular filtration rate (GFR) is a key indicator of renal function. In both clinical practice and pre-clinical research, serum levels of endogenous filtration markers, such as creatinine, are often used to estimate GFR. However, these markers often do not reflect minor changes in renal function. In this study, we therefore set out to evaluate the applicability of transcutaneous GFR (tGFR) measurements to monitor the changes in renal function, as compared to plasma creatinine (pCreatinine), in two models of obstructive nephropathy, namely unilateral ureteral obstruction (UUO) or bilateral ureteral obstruction followed by release (BUO-R) in male Wistar rats. RESULTS: UUO animals showed a significant reduction in tGFR compared to baseline; whereas pCreatinine levels were not significantly changed. In BUO animals, tGFR drops 24 h post BUO and remains lower upon release of the obstruction until day 11. Concomitantly, pCreatinine levels were also increased 24 h after obstruction and 24 h post release, however after 4 days, pCreatinine returned to baseline levels. In conclusion, this study revealed that the tGFR method is superior at detecting minor changes in renal function as compared to pCreatinine measurements.
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Enfermedades Renales , Obstrucción Ureteral , Ratas , Animales , Masculino , Riñón/fisiología , Roedores , Creatinina , Ratas Wistar , Tasa de Filtración GlomerularRESUMEN
Type XXVIII collagen (COL28) is involved in cancer and lung fibrosis. COL28 polymorphisms and mutations might be involved in kidney fibrosis, but the exact role of COL28 in renal fibrosis is unknown. This study explored the function of COL28 in renal tubular cells by examining the expression of COL28 mRNA and the effects of COL28 overexpression in human tubular cells. COL28 mRNA expression and localization were observed in normal and fibrotic kidney tissues from humans and mice using real-time PCR, western blot, immunofluorescence, and immunohistochemistry. The consequences of COL28 overexpression on cell proliferation, migration, cell polarity, and epithelial-to-mesenchymal transition (EMT) induced by TGF-ß1 were examined in human tubular HK-2 cells. COL28 expression was low in human normal renal tissues, mainly observed in the renal tubular epithelial cells and especially in proximal renal tubules. COL28 protein expression in human and mouse obstructive kidney disease was higher than in normal tissues (p < 0.05) and more significant in the UUO2-Week than the UUO1-Week group. The overexpression of COL28 promoted HK-2 cell proliferation and enhanced their migration ability (all p < 0.05). TGF-ß1 (10 ng/ml) induced COL28 mRNA expression in HK-2 cells, decreased E-cadherin and increased α-SMA in the COL28-overexpression group compared with controls (p < 0.05). ZO-1 expression decreased while COL6 increased in the COL28-overexpression group compared with controls (p < 0.05). In conclusion, COL28 overexpression promotes the migration and proliferation of renal tubular epithelial cells. The EMT could also be involved. COL28 could be a therapeutic target against renal- fibrotic diseases.
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Células Epiteliales , Enfermedades Renales , Animales , Humanos , Ratones , Proliferación Celular , Transición Epitelial-Mesenquimal/genética , Fibrosis/genética , Fibrosis/metabolismo , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Túbulos Renales/metabolismo , Túbulos Renales/patología , ARN Mensajero , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Obstructive nephropathy is one of the leading causes of kidney injury and renal fibrosis in pediatric patients. Although considerable advances have been made in understanding the pathophysiology of obstructive nephropathy, most of them were based on animal experiments and a comprehensive understanding of obstructive nephropathy in pediatric patients at the molecular level remains limited. Here, we performed a comparative proteomics analysis of obstructed kidneys from pediatric patients with ureteropelvic junction obstruction and healthy kidney tissues. Intriguingly, the proteomics revealed extensive metabolic reprogramming in kidneys from individuals with ureteropelvic junction obstruction. Moreover, we uncovered the dysregulation of NAD+ metabolism and NAD+-related metabolic pathways, including mitochondrial dysfunction, the Krebs cycle, and tryptophan metabolism, which led to decreased NAD+ levels in obstructed kidneys. Importantly, the major NADase CD38 was strongly induced in human and experimental obstructive nephropathy. Genetic deletion or pharmacological inhibition of CD38 as well as NAD+ supplementation significantly recovered NAD+ levels in obstructed kidneys and reduced obstruction-induced renal fibrosis, partially through the mechanisms of blunting the recruitment of immune cells and NF-κB signaling. Thus, our work not only provides an enriched resource for future investigations of obstructive nephropathy but also establishes CD38-mediated NAD+ decline as a potential therapeutic target for obstruction-induced renal fibrosis.
Asunto(s)
NAD , Obstrucción Ureteral , Animales , Niño , Humanos , Fibrosis , Riñón/metabolismo , NAD/metabolismo , Proteómica , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/metabolismoRESUMEN
Purpose: Acteoside (Act), a phenylethanoid compound that was first isolated from mullein, has been widely used for the investigation of anti-inflammatory and anti-fibrotic effect. However, the mechanism of Act against unilateral ureteral obstruction (UUO)-mediated renal injury is largely unknown. Therefore, this study aimed to explore the effects of Act on UUO rats and possible mechanisms. Methods: A total of 20 Sprague-Dawley (SD) rats were divided randomly into three groups (n ≥ 6): (i) sham-operated group (Sham); (ii) UUO group (UUO+Saline); and (iii) UUO + Act 40 mg/kg/day, (UUO+Act); Continuous gavage administration for 2 weeks postoperatively, while the rats in Sham and UUO+saline groups were given equal amounts of saline. All rats were sacrificed after 14 days, the urine and blood samples were collected for biochemical analysis, the renal tissues were collected for pathological staining and immunohistochemistry. Correlations between individual proteins were analyzed by Pearson correlation analysis. Results: The results of renal function indexes and histopathological staining showed that Act could improve renal function by reducing serum creatinine, blood urea nitrogen and urine protein at the same time, Act could alleviate renal inflammation and fibrosis. In addition, the results of immunohistochemistry showed that Act could reduce the expression of inflammation and kidney injury-related proteins F4/80, Mcp-1, KIM-1 proteins, as well as the expression of fibrosis-related protein α-SMA and ß-catenin. More importantly, Act can also reduce the expression of HMGN1, TLR4 and TREM-1 proteins. Conclusion: These data demonstrate that Act can ameliorate UUO-induced renal inflammation and fibrosis in rats probably through triggering HMGN1/TLR4/TREM-1 pathway.