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Genes May 2024Approximately half of the cases of chronic kidney disease (CKD) in childhood are caused by congenital anomalies of the kidney and urinary tract (CAKUT). Specific genes...
Approximately half of the cases of chronic kidney disease (CKD) in childhood are caused by congenital anomalies of the kidney and urinary tract (CAKUT). Specific genes were identified as having significant importance in regard to the underlying genetic factors responsible for the CAKUT phenotype, and in our research, we focused on analyzing and comparing the expression levels of ectodysplasin A2 receptor (EDA2R), protocadherin9 (PCDH9), and TNF receptor-associated factor 7 (TRAF7) proteins in the cortex and medulla of healthy control kidneys during developmental phases 2, 3, and 4. We also performed an analysis of the area percentages of the mentioned proteins in the cortical and medullary sections of healthy embryonic and fetal kidneys compared to those affected by CAKUT, including duplex kidneys (DK), horseshoe kidneys (HK), hypoplastic kidneys (HYP), and dysplastic kidneys (DYS). We found that the CAKUT candidate gene proteins EDA2R, PCDH9, and TRAF7 are all expressed during normal human kidney development stages. In DYS, the expression of EDA2R was higher than in normal kidneys, likely due to EDA2R's role in apoptosis, which was upregulated in specific cases and could possibly contribute to the formation of DYS. The expression of PCDH9 was lower in HK, which can be attributed to the possible role of PCDH9 in cell migration suppression. Decreased PCDH9 expression is linked to increased cell migration, potentially contributing to the development of HK. The level of TRAF7 expression was reduced in all examined kidney disorders compared to normal kidneys, suggesting that this reduction might be attributed to the crucial role of TRAF7 in the formation of endothelium and ciliogenesis, both of which are essential for normal kidney development. Further research is required to ascertain the function of these proteins in both the typical development of the kidney and in CAKUT.
Topics: Humans; Kidney; Vesico-Ureteral Reflux; Cadherins; Urogenital Abnormalities; Protocadherins; Urinary Tract; Gene Expression Regulation, Developmental
PubMed: 38927638
DOI: 10.3390/genes15060702 -
Current Opinion in Nephrology and... Jun 2024Postnatal renal tubule development is critical to adult kidney function. Several postnatal changes regulate the differentiation and proliferation of renal tubular cells....
PURPOSE OF REVIEW
Postnatal renal tubule development is critical to adult kidney function. Several postnatal changes regulate the differentiation and proliferation of renal tubular cells. Here, we review the literature and our efforts on thick ascending limb (TAL) development in Bartter syndrome (BS).
RECENT FINDINGS
Glomerular filtrate quickly increases after birth, imposing fluid shear stress and circumferential stretch on immature renal tubules. Recent studies showed that kidney organoids under flow (superfusion) have better development of tubular structures and the expression of cilia and solute transporters. These effects are likely mediated by mechanosensors, such as cilia and the piezo1 channel. Improved renal oxygenation and sodium pump-dependent active transport can stimulate mitochondrial respiration and biogenesis. The functional coupling between transport and mitochondria ensures ATP supply for energy-demanding reactions in tubular cells, including cell cycle progression and proliferation. We recently discovered that postnatal renal medulla maturation and TAL elongation are impaired in Clc-k2-deficient BS mice. Primary cultured Clc-k2-deficient TAL cells have G1-S transition and proliferation delay. These developmental defects could be part of the early pathogenesis of BS and worsen the phenotype.
SUMMARY
Understanding how tubular flow and transepithelial ion fluxes regulate renal tubule development may improve the treatment of congenital renal tubulopathies.
PubMed: 38913022
DOI: 10.1097/MNH.0000000000001007 -
JCEM Case Reports Jun 2024Pheochromocytomas (PCCs) and/or paragangliomas (PGLs) are a challenge to diagnose during pregnancy because of elusive signs and testing difficulties. We report a...
Pheochromocytomas (PCCs) and/or paragangliomas (PGLs) are a challenge to diagnose during pregnancy because of elusive signs and testing difficulties. We report a 25-year-old woman with no pertinent medical history who presented to the hospital with hypertension, vision loss, and weakness and was initially diagnosed with preeclampsia. Imaging showed hemangioblastomas in the medulla and thoracic spine, pancreatic cysts, and a renal cyst. The endocrinology service was consulted for possible PCCs associated with von Hippel-Lindau disease (VHL). Serum and urine normetanephrine levels were elevated despite the lack of overt PCCs/PGLs seen on magnetic resonance imaging and magnetic resonance angiography. The patient was medically managed with doxazosin and then labetalol. Despite successful resection of the hemangioblastoma in the medulla, the patient suffered respiratory distress requiring tracheostomy and venous-venous extracorporeal membrane oxygenation (V-V ECMO) and fetal demise. After 3 months, the patient was discharged to rehabilitation. Follow-up genetics were heterozygous for VHL and Lynch syndrome. DOTATATE positron emission tomography/computed tomography scan showed a small hepatic focus of a maximum standard uptake value of 12.1. Altogether, this case illustrates the importance of prompt diagnosis and proper management of PCCs/PGLs during pregnancy and incorporating genetic information during surveillance to lower morbidity and mortality.
PubMed: 38911362
DOI: 10.1210/jcemcr/luae097 -
The Knee Jun 2024Periprosthetic joint infections (PJIs) are commonly treated with two-stage revision surgery utilising antibiotic-loaded spacers; however, antibiotic release from spacers...
BACKGROUND
Periprosthetic joint infections (PJIs) are commonly treated with two-stage revision surgery utilising antibiotic-loaded spacers; however, antibiotic release from spacers is limited and usually drops below effective levels a few days after placement. This study compared high-dose and standard-dose vancomycin-loaded spacers in terms of efficacy, safety, and overall treatment duration in a rat periprosthetic joint infection model.
METHODS
Thirty male Wistar albino rats (8-10 weeks old, 300-320 g) were housed individually at standard conditions. A periprosthetic infection model was established in the right knee of the rats using methicillin-resistant Staphylococcus aureus (MRSA) -contaminated Kirschner wires. Two weeks later, the infection was verified, and the Kirschner wires were removed. Rats were randomly divided into three groups (n = 10): standard-dose (SVanc) and high-dose (HVanc) vancomycin groups had 2.5 and 7.5% vancomycin in their spacers, respectively, while the control group had no spacers. All groups received intramuscular (IM) vancomycin and gentamicin for 4 weeks after spacer implantation. Microbiological counts and vancomycin levels in the blood and joint flush samples were measured, and histopathological assessments were conducted on the femur and kidneys.
RESULTS
After spacer implantation, MRSA was eliminated in the HVanc group with 4 weeks of treatment, while the SVanc group required 6 weeks of treatment (P < 0.001). Histopathological findings of the femoral medulla and cortical samples were better in the HVanc group compared with other groups (P = 0.007). Vancomycin levels in serum remained within safe limits in all groups, and kidney damage was not observed.
CONCLUSION
The use of high-dose vancomycin spacers might accelerate the transition period, which in turn reduces the duration of systemic antibiotic use and mitigates the risk of nephrotoxicity. Thus, this method may decrease the medical costs associated with PJI treatment.
PubMed: 38909590
DOI: 10.1016/j.knee.2024.06.004 -
Insights Into Imaging Jun 2024To assess renal interstitial fibrosis (IF) using diffusion MRI approaches, and explore whether corticomedullary difference (CMD) of diffusion parameters, combination...
OBJECTIVE
To assess renal interstitial fibrosis (IF) using diffusion MRI approaches, and explore whether corticomedullary difference (CMD) of diffusion parameters, combination among MRI parameters, or combination with estimated glomerular filtration rate (eGFR) benefit IF evaluation.
METHODS
Forty-two patients with chronic kidney disease were included, undergoing MRI examinations. MRI parameters from apparent diffusion coefficient (ADC), intra-voxel incoherent motion (IVIM), diffusion kurtosis imaging (DKI), and diffusion-relaxation correlated spectrum imaging (DR-CSI) were obtained both for renal cortex and medulla. CMD of these parameters was calculated. Pathological IF scores (1-3) were obtained by biopsy. Patients were divided into mild (IF = 1, n = 23) and moderate-severe fibrosis (IF = 2-3, n = 19) groups. Group comparisons for MRI parameters were performed. Diagnostic performances were assessed by the receiver operator's curve analysis for discriminating mild from moderate-severe IF patients.
RESULTS
Significant inter-group differences existed for cortical ADC, IVIM-D, IVIM-f, DKI-MD, DR-CSI V, and DR-CSI V. Significant inter-group differences existed in ΔADC, ΔMD, ΔV, ΔV, ΔQ and ΔQ. Among the cortical MRI parameters, V displayed the highest AUC = 0.849, while ADC, f, and MD also showed AUC > 0.8. After combining cortical value and CMD, the diagnostic performances of the MRI parameters were slightly improved except for IVIM-D. Combining V with f brings the best performance (AUC = 0.903) among MRI bi-variant models. A combination of cortical V, ΔADC, and eGFR brought obvious improvement in diagnostic performance (AUC 0.963 vs 0.879, specificity 0.826 vs 0.896, and sensitivity 1.000 vs 0.842) than eGFR alone.
CONCLUSION
Our study shows promising results for the assessment of renal IF using diffusion MRI approaches.
CRITICAL RELEVANCE STATEMENT
Our study explores the non-invasive assessment of renal IF, an independent and effective predictor of renal outcomes, by comparing and combining diffusion MRI approaches including compartmental, non-compartmental, and model-free approaches.
KEY POINTS
Significant difference exists for diffusion parameters between mild and moderate-severe IF. Generally, cortical parameters show better performance than corresponding CMD. Bi-variant model lifts the diagnostic performance for assessing IF.
PubMed: 38900336
DOI: 10.1186/s13244-024-01736-2 -
Neuroscience Bulletin Jun 2024The kidneys are essential organs that help maintain homeostasis, and their function is regulated by the neural system. Despite the anatomical multi-synaptic connection...
The kidneys are essential organs that help maintain homeostasis, and their function is regulated by the neural system. Despite the anatomical multi-synaptic connection between the central autonomic nuclei and the kidneys, it remains unclear whether there are any variations in neural connections between the nervous systems and the renal cortex and medulla in male and female mice. Here, we used the pseudorabies virus to map the central innervation network of the renal cortex and medulla in both sexes. The data revealed that specific brain regions displayed either a contralateral-bias or ipsilateral-bias pattern while kidney-innervating neurons distributed symmetrically in the midbrain and hindbrain. Sex differences were observed in the distribution of neurons connected to the left kidney, as well as those connected to the renal cortex and medulla. Our findings provide a comprehensive understanding of the brain-kidney network in both males and females and may help shed light on gender differences in kidney function and disease susceptibility in humans.
PubMed: 38896358
DOI: 10.1007/s12264-024-01240-z -
Urolithiasis Jun 2024Alexander Randall first published renal papillary tip findings from stone formers in 1937, paving the way for endoscopic assessment to study stone pathogenesis. We... (Review)
Review
Alexander Randall first published renal papillary tip findings from stone formers in 1937, paving the way for endoscopic assessment to study stone pathogenesis. We performed a literature search to evaluate the safety of papillary tip biopsy and clinical insights gained from modern renal papillary investigations. A search on the topic of renal papillary biopsy provided an overview of Randall's plaques (RP), classification systems for renal papillary grading, and a summary of procedure type, complications, and outcomes. Within 26 identified manuscripts, 660 individuals underwent papillary tip biopsy percutaneously (n = 562), endoscopically (n = 37), or unspecified (n = 23). Post-operative hemoglobin changes were similar to controls. One individual (0.2%) reported fever > 38°, and long-term mean serum creatinine post-biopsy (n = 32) was unchanged. Biopsies during ureteroscopy or PCNL added ~20-30 min of procedure time. Compared to controls, papillary plaque-containing tissue had upregulation in pro-inflammatory genes, immune cells, and cellular apoptosis. Urinary calcium and papillary plaque coverage were found to differ between RP and non-RP stone formers, suggesting differing underlying pathophysiology for these groups. Two renal papillary scoring systems have been externally validated and are used to classify stone formers. Overall, this review shows that renal papillary biopsies have a low complication profile with high potential for further research. Systematic adaption of a papillary grading scale, newer tissue analysis techniques, and the development of animal models of Randall's plaque may allow further exploration of plaque pathogenesis and identify targets for prevention therapies in patients with nephrolithiasis.
Topics: Humans; Kidney Calculi; Biopsy; Ureteroscopy; Kidney Medulla; Nephrolithotomy, Percutaneous
PubMed: 38888601
DOI: 10.1007/s00240-024-01596-x -
Cureus May 2024Renomedullary interstitial cell tumors (RMICTs) are rare benign renal tumors that arise from the renal medulla. They are rarely symptomatic and are mostly discovered...
Renomedullary interstitial cell tumors (RMICTs) are rare benign renal tumors that arise from the renal medulla. They are rarely symptomatic and are mostly discovered incidentally. Radiologically, their co-presence ipsilaterally in the background of a larger mass introduces a miscellaneous presentation that raises the suspicion of metastatic disease. A characteristic presentation does not exist. Therefore, an individualized, patient-centered approach should be tailored depending on the nature of the presentation. We report the clinical, radiological, and histopathological presentation of a 46-year-old woman presenting with an RMICT in the background of a renal oncocytoma.
PubMed: 38887327
DOI: 10.7759/cureus.60531 -
PloS One 2024Acute kidney injury (AKI) is a common complication of septic shock and together these conditions carry a high mortality risk. In septic patients who develop severe AKI,... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Acute kidney injury (AKI) is a common complication of septic shock and together these conditions carry a high mortality risk. In septic patients who develop severe AKI, renal cortical perfusion is deficient despite normal macrovascular organ blood flow. This intra-renal perfusion abnormality may be amenable to pharmacological manipulation, which may offer mechanistic insight into the pathophysiology of septic AKI. The aim of the current study is to investigate the effects of vasopressin and angiotensin II on renal microcirculatory perfusion in a cohort of patients with septic shock.
METHODS AND ANALYSIS
In this single centre, mechanistically focussed, randomised controlled study, 45 patients with septic shock will be randomly allocated to either of the study vasopressors (vasopressin or angiotensin II) or standard therapy (norepinephrine). Infusions will be titrated to maintain a mean arterial pressure (MAP) target set by the attending clinician. Renal microcirculatory assessment will be performed for the cortex and medulla using contrast-enhanced ultrasound (CEUS) and urinary oxygen tension (pO2), respectively. Renal macrovascular flow will be assessed via renal artery ultrasound. Measurement of systemic macrovascular flow will be performed through transthoracic echocardiography (TTE) and microvascular flow via sublingual incident dark field (IDF) video microscopy. Measures will be taken at baseline, +1 and +24hrs following infusion of the study drug commencing. Blood and urine samples will also be collected at the measurement time points. Longitudinal data will be compared between groups and over time.
DISCUSSION
Vasopressors are integral to the management of patients with septic shock. This study aims to further understanding of the relationship between this therapy, renal perfusion and the development of AKI. In addition, using CEUS and urinary pO2, we hope to build a more complete picture of renal perfusion in septic shock by interrogation of the constituent parts of the kidney. Results will be published in peer-reviewed journals and presented at academic meetings.
TRIAL REGISTRATION
The REPERFUSE study was registered on Clinical Trials.gov (NCT06234592) on the 30th Jan 24.
Topics: Humans; Shock, Septic; Vasoconstrictor Agents; Microcirculation; Acute Kidney Injury; Kidney; Vasopressins; Angiotensin II; Male; Female; Norepinephrine; Renal Circulation; Middle Aged; Adult
PubMed: 38870103
DOI: 10.1371/journal.pone.0304227 -
American Journal of Physiology. Renal... Jun 2024Chronic kidney disease (CKD) is characterized by inflammation and fibrosis in the kidney. Renal biopsies and estimated glomerular filtration rate (eGFR) remain the...
Chronic kidney disease (CKD) is characterized by inflammation and fibrosis in the kidney. Renal biopsies and estimated glomerular filtration rate (eGFR) remain the standard of care, but these endpoints have limitations in detecting the stage, progression, and spatial distribution of fibrotic pathology in the kidney. MRI diffusion tensor imaging (DTI) has emerged as a promising non-invasive technology to evaluate renal fibrosis both in clinical and preclinical studies. However, these imaging studies have not systematically identified fibrosis particularly deeper in the kidney where biopsy sampling is limited, or completed an extensive analysis of whole organ histology, blood biomarkers, and gene expression to evaluate the relative strengths and weaknesses of MRI for evaluating renal fibrosis. In this study, we performed DTI in the sodium oxalate mouse model of CKD. The DTI parameters fractional anisotropy, apparent diffusion coefficient, and axial diffusivity were compared between the control and oxalate groups with region-of-interest (ROI) analysis to determine changes in the cortex and medulla. Additionally, voxel-based analysis (VBA) was implemented to systematically identify local regions of injury over the whole kidney. DTI parameters were found to be significantly different in the medulla by both ROI analysis and VBA, which also spatially matched with collagen III IHC. The DTI parameters in this medullary region exhibited moderate to strong correlations with histology, blood biomarkers, hydroxyproline and gene expression. Our results thus highlight the sensitivity of DTI to the heterogeneity of renal fibrosis and importance of whole kidney non-invasive imaging.
PubMed: 38867676
DOI: 10.1152/ajprenal.00099.2024