Obstructed Kidneys Research Articles

Renal tubular function and morphology revealed in kidney without labeling using three-dimensional dynamic optical coherence tomography

Renal tubule has distinct metabolic features and functional activity that may be altered during kidney disease. In this paper, we present label-free functional activity imaging of renal tubule in normal and obstructed mouse kidney models using three-dimensional (3D) dynamic optical coherence tomography (OCT) ex vivo. To create an obstructed kidney model, we ligated the ureter of the left kidney for either 7 or 14 days. Two different dynamic OCT (DOCT) methods were implemented to access the slow and fast activity of the renal tubules: a logarithmic intensity variance (LIV) method and a complex-correlation-based method. Three-dimensional DOCT data were acquired with a 1.3 upmum swept-source OCT system and repeating raster scan protocols. In the normal kidney, the renal tubule appeared as a convoluted pipe-like structure in the DOCT projection image. Such pipe-like structures were not observed in the kidneys subjected to obstruction of the ureter for several days. Instead of any anatomical structures, a superficial high dynamics appearance was observed in the perirenal cortex region of the obstructed kidneys. These findings suggest that volumetric LIV can be used as a tool to investigate kidney function during kidney diseases.

Associations between maternal chronic diseases and congenital anomalies of the kidney and urinary tract in offspring: a population-based cohort study.

The relationship between maternal chronic diseases and congenital anomalies of the kidneys and urinary tract (CAKUT) in offspring still needs elucidation. This study aimed to comprehensively evaluate the associations between maternal chronic disease and CAKUT in their offspring. Data of mothers and children were extracted from the Taiwan Maternal and Child Health Database and National Health Insurance Research Database. The concept of developmental origins of health and disease (DOHaD) was used to select maternal chronic diseases. The study cohort included 1196175 mothers and 1628706 offspring. Analysis showed that maternal chronic diseases, especially type 1 diabetes, type 2 diabetes, gestational diabetes, connective tissue disorders and CAKUT were highly associated with CAKUT in the offspring. Higher maternal age, abnormal birthweight (>3500g or <2500g), gestational age <36weeks and birth order <2 were all associated with a higher risk of CAKUT. Maternal chronic hypertension and taking angiotensin-related drugs increased the odds ratios of obstructive kidney disease in the offspring. Offspring tended to have the same type of CAKUT as their mothers. Maternal chronic diseases, older maternal age and abnormal birthweight are risk factors for CAKUT. Also, a percentage of patients with CAKUT were not full-term newborns. Results support prenatal counselling and health management of pregnant women with chronic diseases and extra care for infants with a high risk of anomalies. It is strongly recommended that prevention of CAKUT in offspring should start with care of the mothers' prenatal chronic diseases.

Renal Fibrosis Is Alleviated through Targeted Inhibition of IL-11–Induced Renal Tubular Epithelial-to-Mesenchymal Transition

Renal fibrosis is a pathologic process that leads to irreversible renal failure without effective treatment. Epithelial-to-mesenchymal transition (EMT) plays a key role in this process. The current study found that aberrant expression of IL-11 is critically involved in tubular EMT. IL-11 and its receptorsubunitalpha-1 (IL-11Rα1) were significantly induced in renal tubular epithelial cells (RTECs) in unilateral ureteral obstruction (UUO) kidneys, co-localized with transforming growth factor-β1. IL-11 knockdown ameliorated UUO-induced renal fibrosis invivo and transforming growth factor-β1-induced EMT invitro. IL-11 intervention directly induced the transdifferentiation of RTECs to the mesenchymal phenotype and increased the synthesis of profibrotic mediators. The EMT response induced by IL-11 was dependent on the sequential activation of STAT3 and extracellular signal-regulated kinase 1/2 signaling pathways and the up-regulation of metadherin in RTECs. Micheliolide (MCL) competitively inhibited the binding of IL-11 with IL-11Rα1, suppressing the activation of STAT3 and extracellular signal-regulated kinase 1/2-metadherin pathways, ultimately inhibiting renal tubular EMT and interstitial fibrosis induced by IL-11. In addition, treatment with dimethylaminomicheliolide, a pro-drug of MCL for invivo use, significantly ameliorated renal fibrosis exacerbated by IL-11 in the UUO model. These findings suggest that IL-11 is a promising target in renal fibrosis and that MCL/dimethylaminomicheliolide exerts its antifibrotic effect by suppressing IL-11/IL-11Rα1 interaction and blocking its downstream effects.

Abstract P376: Collecting Duct Renin And Its Receptor Contributes To Unilateral Ureteral Obstruction-induced Kidney Injury Via Activation Of The Intrarenal Ras

The collecting duct (CD) is well known for its role in fine-tuning urinary excretion of electrolytes and water. Emerging evidence suggests a potential role played by the CD in immunity and renal injury but the underlying mechanism largely remains elusive. Within the CD, (pro)renin receptor (PRR) via site-1 protease (S1P)-derived soluble PRR interacts with renin controls the intrarenal renin-angiotensin system (RAS) to regulate Na+ and water balance and blood pressure. The present study attempted to employ mouse models of CD-specific deletion of PRR and renin (CD PRR KO and CD renin KO, respectively) and a specific S1P inhibitor PF-429242 (PF) to explore the pathogenic role of this local system in renal injury induced by unilateral ureteral obstruction (UUO). Male 3-4-month-old CD PRR KO and CD renin KO, and their respective floxed controls were subjected to UUO surgery or sham operation for 3 days, followed by analysis of renal fibrosis, inflammation, and indices of the intrarenal RAS. Male 3-4-month-old C57BL/6 mice were subjected to the same surgical procedures and infused with vehicle or PF at 20 mg/kg/day via minipump for 3 days, followed by analysis of the same parameters. 3-day UUO in floxed mice induced renal abundance of fibronectin and α-SMA by 8.6 folds and 5.8 folds, respectively, as assessed by immunoblotting analysis. qRT-PCR detected similar magnitude of increases in mRNA expression of fibronectin, α-SMA, as well as collagen III, collagen I, and TGF-β in the obstructed kidneys. Similar results were obtained by Trichrome Masson staining. In parallel, the obstructed kidney exhibited 4-5-fold increases in renal medullary renin mRNA, renin activity, and active renin content contrasting to unaltered renin levels in the renal cortex. CD-specific deletion of PRR and renin induced comparable attenuation of various indices of renal fibrosis, inflammation, renal medullary renin levels so did PF treatment. UUO induced a 2-fold increase in plasma sPRR, which was completely blocked by PF treatment. Taken together, our results demonstrated that CD PRR/sPRR-dependent activation of renin represents a key determinant of the intrarenal RAS and thus obstruction-induced renal inflammation and fibrosis.

Predictors of SARS-CoV-2 Infection and Severe and Lethal COVID-19 after Three Years of Follow-Up: A Population-Wide Study.

In this cohort study, the general population of an Italian Province was followed for three years after the start of the pandemic, in order to identify the predictors of SARS-CoV-2 infection and severe or lethal COVID-19. All the National Healthcare System information on biographical records, vaccinations, SARS-CoV-2 swabs, COVID-19 cases, hospitalizations and co-pay exemptions were extracted from 25 February 2020 to 15 February 2023. Cox proportional hazard analysis was used to compute the relative hazards of infection and severe or lethal COVID-19, adjusting for age, gender, vaccine status, hypertension, diabetes, major cardiovascular diseases (CVD), chronic obstructive pulmonary disease (COPD), kidney disease or cancer. Among the 300,079 residents or domiciled citizens, 41.5% had ≥1 positive swabs during the follow-up (which lasted a mean of 932 days). A total of 3.67% of the infected individuals experienced severe COVID-19 (n = 4574) and 1.76% died (n = 2190). Females, the elderly and subjects with diabetes, CVD, COPD, kidney disease and cancer showed a significantly higher risk of SARS-CoV-2 infection. The likelihood of severe or lethal COVID-19 was >90% lower among the youngest, and all comorbidities were independently associated with a higher risk (ranging from +28% to +214%) of both outcomes. Two years after the start of the immunization campaign, the individuals who received ≥2 doses of COVID-19 vaccines still showed a significantly lower likelihood of severe or lethal disease, with the lowest risk observed among subjects who received at least one booster dose.

Decreased percent change in renal pelvis diameter on diuretic functional magnetic resonance urography following administration of furosemide may help characterize unilateral uretero-pelvic junction obstruction

A well-established definition of obstruction in the setting of congenital hydronephrosis is lacking. Multiple imaging modalities and radiographic characteristics or parameters have been described to help confirm the diagnosis of ureteropelvic junction obstruction (UPJO). We sought to evaluate the change in anterior-posterior renal pelvic diameter (APRPD) following furosemide administration in patients with unilateral hydronephrosis and confirmed UPJO on functional magnetic resonance urography (fMRU) who underwent pyeloplasty. There were 49 patients who met inclusion criteria (11 females, 38 males; average age 2.2 years, SD 3.4 years) from February 2006 to September 2020, diagnosed with unilateral hydronephrosis (SFU Grade 3-4) who underwent fMRU prior to pyeloplasty for confirmed UPJO. 29 of the included patients also underwent a post-pyeloplasty fMRU. A weight-adjusted dose of 1mg/kg of furosemide (max 20mg/kg) was administered intravenously. Two board-certified pediatric radiologists measured the APRPD of the obstructed and non-dilated kidneys prior to pyeloplasty and APRPD of the hydronephrotic kidneys on the post-pyeloplasty follow up fMRUs. Measurements were performed on images prior to and approximately 30min following furosemide injection. The average APRPD before furosemide injection in the obstructed kidney prior to pyeloplasty was 26.3mm (SD 9.0mm) compared to the non-dilated (not obstructed) kidney measurement of 5.1mm (SD 3.6mm) (p<0.001). Following administration of furosemide, the average APRPD was 31.4mm (SD 8.8mm) in the obstructed kidney, and 7.8mm (SD 4.1mm) in the non-dilated kidney (p<0.001). After pyeloplasty, the pre-furosemide APRPD measurement was 17.8mm (SD 11mm), which was significantly less compared to the pre-pyeloplasty APRPD (p<0.001). The post-pyeloplasty, post-furosemide APRPD measurement was 25.8mm (SD 12mm), also significantly less compared to the pre-pyeloplasty measurement (p=0.02). The changes in APRPD in the obstructed kidney prior to pyeloplasty was 5.1mm (SD 3.5mm) and after pyeloplasty was 8mm (SD 4.6mm) (p=0.002). Change in APRPD in the non-dilated kidney was 2.7mm (SD 2.3mm). Percent APRPD change in the obstructed kidney was 22.9% (SD 18.5%), which was significantly less than 33.3% (SD 22.1%) in the post-pyeloplasty kidney (p=0.028) and 82.8% (SD 87.9%) in the non-dilated kidney (p<0.001). A relatively smaller change in APRPD on fMRU following administration of furosemide in the setting of UPJO may serve as another predictive characteristic of obstructed kidneys.

Does the kidney actually swell during an acute urinary tract obstruction?

The appearance of renal swelling during an acute obstruction of the urinary tract could be caused by hydronephrosis or an increase of the parenchymal volume. To the best of our knowledge no studies have been performed regarding renal parenchymal volume change during an acute urinary tract obstruction. To investigate the change in renal parenchymal volume during an acute urinary tract obstruction and to correlate any such volume change to the degree of secondary signs of obstruction. In total, 20 patients with obstructive ureterolithiasis were retrospectively and randomly included. Two observers measured the parenchymal volume of the obstructed and the contralateral kidney in CT examinations before, during, and after obstruction. Hydronephrosis, hydroureter, perirenal stranding, and thickening of the renal fascia were graded and correlated to volume change. A decreased volume was noted after obstruction in the obstructed kidneys (-24%) (P < 0.0001) and in the contralateral kidneys (-5%) (P = 0.0110) with a positive correlation of change in volume (P = 0.011). The volume of the obstructed kidneys was larger than the contralateral kidneys during obstruction (P < 0.0001) but not after obstruction (P = 0.559). No significant difference in volume was found before compared to after obstruction. Secondary signs of obstruction did not correlate to volume change. The parenchymal volume increases in the obstructed kidneys as well as in the contralateral kidneys during obstruction. The increase in volume was larger in the obstructed kidneys compared to the contralateral kidneys. After obstruction the kidneys regained their original volume. Secondary signs did not correlate to volume change.

A combination of 5/6-nephrectomy and unilateral ureteral obstruction model accelerates progression of remote organ fibrosis in chronic kidney disease.

Chronic kidney disease (CKD) involves progressive renal fibrosis, which gradually reduces kidney function and often causes various complications in extrarenal tissues. Therefore, we investigated fibrogenesis in extrarenal tissues (heart, liver, and lungs) in different experimental CKD models, such as the 5/6-nephrectomy (5/6 Nx), unilateral ureteral obstruction (UUO), and a combination (2/3 Nx + UUO). We evaluated the degree of fibrogenesis in kidneys and extrarenal tissues by histological analysis and quantification of fibrosis-related gene and protein expression. To elucidate the fibrosis mechanisms observed in 2/3 Nx + UUO mice, we evaluated the effect of indoxyl sulfate (IS), a typical uremic toxin accumulated in CKD, and transforming growth factor-β (TGF-β), a fibrosis-related factor, on fibrosis using human hepatoma (HepG2) and RAW264.7 cells. A significant decline in renal function was observed in the 5/6 Nx and 2/3 Nx + UUO models, whereas a significant increase in renal fibrosis was observed only in the obstructed kidneys. Notable amount of fibrosis was induced in the liver and heart in the 2/3 Nx + UUO model, with the induction of macrophage infiltration and increased tissue IS and TGF-β levels. In agreement with the results of in vivo experiments, co-stimulation with IS, TGF-β, and macrophage-conditioned medium increased the expression of fibrogenic genes in HepG2 cells. We demonstrated that the 2/3 Nx + UUO model induced both loss of renal function and renal fibrosis in the earlier stages, providing a novel CKD model that induces remote organ fibrosis in a shorter time.

Atorvastatin reduces renal interstitial fibrosis caused by unilateral ureteral obstruction through inhibiting the transcriptional activity of YAP

Renal interstitial fibrosis is the primary pathological basis for the progression and development of various chronic kidney diseases, ultimately leading to renal failure. Obstructive kidney disease caused by conditions such as kidney stones, is a common cause of renal fibrosis. The Hippo pathway is a crucial signaling pathway that senses mechanical forces and is involved in the pathophysiology of fibrosis. In this study, we established a mouse model of obstructive kidney disease induced by unilateral ureteral obstruction (UUO). The UUO procedure significantly upregulated YAP and fibrosis-related gene expression in a time-dependent manner. Morphologically, the renal fibrotic lesions associated with hydronephrosis progressively worsened over time in the UUO group. Atorvastatin, which is widely used to lower blood cholesterol levels, has recently been shown to inhibit Yes1 associated protein (YAP). We treated UUO mice with atorvastatin for 3 and 10 days and observed a decrease in the expression of YAP and fibrosis-related genes at the mRNA and protein levels, along with a reduction in the renal fibrosis analyzed by Masson's staining. These findings suggest that atorvastatin may serve as a preventive agent for fibrosis associated with obstructive kidney disease.

Systemic Mutation of Ncf1 Ameliorates Obstruction-Induced Renal Fibrosis While Macrophage-Rescued NCF1 Further Alleviates Renal Fibrosis.

Aims: NCF1, a subunit of the NADPH oxidase 2 (NOX2), first described the expression in neutrophils and macrophages and participated in the pathogenesis from various systems. However, there are controversial findings on the role of NCF1 in different kinds of kidney diseases. In this study, we aim to pinpoint the specific role of NCF1 in the progression of renal fibrosis induced by obstruction. Results: In this study, NCF1 expression was upregulated in kidney biopsies of chronic kidney disease patients. The expression level of all subunits of the NOX2 complex was also significantly increased in the unilateral ureteral obstruction (UUO) kidney. Then, we used wild-type mice and Ncf1 mutant mice (Ncf1m1j mice) to perform UUO-induced renal fibrosis. Results demonstrated that Ncf1m1j mice exhibited mild renal fibrosis but increased macrophages count and CD11b+Ly6Chi macrophage proportion. Next, we compared the renal fibrosis degree between Ncf1m1j mice and Ncf1 macrophage-rescued mice (Ncf1m1j.Ncf1Tg-CD68 mice). We found that rescuing NCF1 expression in macrophages further alleviated renal fibrosis and decreased macrophage infiltration in the UUO kidney. In addition, flow cytometry data showed fewer CD11b+Ly6Chi macrophages in the kidney of the Ncf1m1j.Ncf1Tg-CD68 group than the Ncf1m1j group. Innovation: We first used the Ncf1m1j mice and Ncf1m1j.Ncf1Tg-CD68 mice to detect the role of NCF1 in the pathological process of renal fibrosis induced by obstruction. Also, we found that NCF1 expressed in different cell types exerts opposing effects on obstructive nephropathy. Conclusion: Taken together, our findings support that systemic mutation of Ncf1 ameliorates renal fibrosis induced by obstruction, and rescuing NCF1 in macrophages further alleviates renal fibrosis.

Comparison of outcomes of self-expanding versus balloon-expandable valves for transcatheter aortic valve replacement: a meta-analysis of randomized and propensity-matched studies

BackgroundThe postoperative outcomes of transcatheter aortic valve replacement (TAVR) with the new generation of self-expanding valves (SEV) and balloon-expandable valves (BEV) remain uncertain.MethodsWe conducted a meta-analysis based on randomized controlled trials (RCTs) and propensity score-matched (PSM) studies to evaluate the performance of the new generation TAVR devices, with a focus on Edwards SAPIEN 3/Ultra BEV, Medtronic Evolut R/PRO SEV, and Boston ACURATE neo SEV. Our primary endpoints were mortality and complications at both 30 days and one year post-operation.ResultsA total of 4 RCTs and 14 PSM studies were included. Our findings showed no significant difference between SEV and BEV regarding 30-day and 1-year mortality rates. ACURATE SEV required less permanent pacemaker implantation (PPI) at 30-day as compared to SAPIEN BEV, while Evolut SEV required a higher rate of PPI than SAPIEN BEV. The incidence of stroke, major or life-threatening bleeding (MLTB), major vascular complications (MVC), coronary artery obstruction (CAO) and acute kidney injury (AKI) did not differ significantly between the two groups. SEV had a larger effective orifice area (EOA) and lower mean transvalvular gradients (MPG) compared to BEV. However, there was an increased risk of paravalvular leakage (PVL) associated with SEV.ConclusionsIn terms of 30-day mortality, stroke, bleeding, MVC, AKI, CAO, and one-year mortality, there was comparability between the two valve types following TAVR. SEV was associated with better hemodynamic outcomes, except for a higher incidence of PVL. Compared to SAPIEN BEV, ACURATE SEV had a lower risk of PPI at 30 days, while Evolut SEV was associated with a higher risk of PPI. These findings underscore the importance of personalized valve selection.

An integrative latent class model of heterogeneous data modalities for diagnosing kidney obstruction.

Radionuclide imaging plays a critical role in the diagnosis and management of kidney obstruction. However, most practicing radiologists in US hospitals have insufficient time and resources to acquire training and experience needed to interpret radionuclide images, leading to increased diagnostic errors. To tackle this problem, Emory University embarked on a study that aims to develop a computer-assisted diagnostic (CAD) tool for kidney obstruction by mining and analyzing patient data comprised of renogram curves, ordinal expert ratings on the obstruction status, pharmacokinetic variables, and demographic information. The major challenges here are the heterogeneity in data modes and the lack of gold standard for determining kidney obstruction. In this article, we develop a statistically principled CAD tool based on an integrative latent class model that leverages heterogeneous data modalities available for each patient to provide accurate prediction of kidney obstruction. Our integrative model consists of three sub-models (multilevel functional latent factor regression model, probit scalar-on-function regression model, and Gaussian mixture model), each of which is tailored to the specific data mode and depends on the unknown obstruction status (latent class). An efficient MCMC algorithm is developed to train the model and predict kidney obstruction with associated uncertainty. Extensive simulations are conducted to evaluate the performance of the proposed method. An application to an Emory renal study demonstrates the usefulness of our model as a CAD tool for kidney obstruction.

HCK induces macrophage activation to promote renal inflammation and fibrosis via suppression of autophagy

Renal inflammation and fibrosis are the common pathways leading to progressive chronic kidney disease (CKD). We previously identified hematopoietic cell kinase (HCK) as upregulated in human chronic allograft injury promoting kidney fibrosis; however, the cellular source and molecular mechanisms are unclear. Here, using immunostaining and single cell sequencing data, we show that HCK expression is highly enriched in pro-inflammatory macrophages in diseased kidneys. HCK-knockout (KO) or HCK-inhibitor decreases macrophage M1-like pro-inflammatory polarization, proliferation, and migration in RAW264.7 cells and bone marrow-derived macrophages (BMDM). We identify an interaction between HCK and ATG2A and CBL, two autophagy-related proteins, inhibiting autophagy flux in macrophages. In vivo, both global or myeloid cell specific HCK-KO attenuates renal inflammation and fibrosis with reduces macrophage numbers, pro-inflammatory polarization and migration into unilateral ureteral obstruction (UUO) kidneys and unilateral ischemia reperfusion injury (IRI) models. Finally, we developed a selective boron containing HCK inhibitor which can reduce macrophage pro-inflammatory activity, proliferation, and migration in vitro, and attenuate kidney fibrosis in the UUO mice. The current study elucidates mechanisms downstream of HCK regulating macrophage activation and polarization via autophagy in CKD and identifies that selective HCK inhibitors could be potentially developed as a new therapy for renal fibrosis.

Cells of the renin lineage promote kidney regeneration post-release of ureteral obstruction in neonatal mice.

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. 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. 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. CoRL play a role in the regeneration of the kidneys post-relief of obstruction.

#4161 DELETION OF PROTEIN TYROSINE KINASES 4A1 AMELIORATE RENAL FIBROSIS INDUCED BY UUO IN MICE

Abstract Background and Aims Inhibitors of protein tyrosine kinases has been investigated as potential anti-fibrotic agents. protein tyrosine kinases 4A1 belongs to a sub-class of three prenylated protein tyrosine kinases. protein tyrosine kinases 4A1 has known as promoting growth and migration of tumor cells. The role protein tyrosine kinases 4A1 has little known in kidney. We evaluated whether the protein tyrosine kinases 4A1 could be target of renal fibrosis. Method 10 weeks old male background protein tyrosine kinases 4A1 KO mice and wild type mice were divided into 4 groups; wild, protein tyrosine kinases 4A1 KO, wild with unilateral ureteral obstruction, and protein tyrosine kinases 4A1 KO with unilateral ureteral obstruction. Mice were sacrificed at 7 days after surgery and kidney tissue were collected. Molecular study and Histologic examination were performed. Results Protein tyrosine kinases 4A1 KO with unilateral ureteral obstruction mice showed decrease of renal tubule-interstitial damage and fibrosis compared to wild type unilateral ureteral obstruction mice. protein tyrosine kinases 4A1 KO with unilateral ureteral obstruction reduced the renal expression of α-SMA and TGF-β in unilateral ureteral obstruction kidney, compared to wild type with unilateral ureteral obstruction mice. Wild type with unilateral ureteral obstruction kidney showed decrease of renal expression of E-cadherin, compared to sham mice. However, protein tyrosine kinases 4A1 KO unilateral ureteral obstruction showed increase of renal expression of E-cadherin, compared to Wild type unilateral ureteral obstruction mice. In vitro, silencing of protein tyrosine kinases 4A1 in TGF-β treated HK2 cell showed increase of E-cadherin and decrease of phosphorylation of AKT and GSK3ß. Conclusion Protein tyrosine kinases 4A1 KO ameliorate renal fibrosis in unilateral ureteral obstruction kidney.

Atypical clinical presentation and management of urinary stone disease in non-verbal non-ambulatory children

Management of kidney stones primarily depends on various factors such as the presence of urinary tract obstruction, pain, stone size, location, impact on renal function, and the existence of infection. Renal colic is the classic presentation of an obstructive kidney stone. However, in this study, we present a cohort of non-verbal non-ambulatory (NVNA) patients who exhibit a distinct and uncommon presentation of kidney stones due to their medical conditions. Information about kidney stone disease in this gropup of complex pediatric patients is, scarce and their associated risk factors are not well understood. Therefore, we aim to summarize the clinical presentation, and management challenges in this unique group of NVNA patients to identify potential variables for prospective studies. A retrospective chart review was completed for all NVNA patients seen at the pediatric multidisciplinary kidney stone clinic between July 2020 to August 2022. Demographic variables, clinical presentation data, metabolic evaluation, radiological imaging, and surgical management was included for analysis. A total of 224 pediatric patients were referred to the multidisciplinary stone clinic. Of those, 27 were identified to be NVNA. The most common primary diagnosis was Cerebral Palsy followed by Lennox-Gastaut syndrome. Average age at first kidney stone presentation was 11.5 years±5.7 years. An obstructing stone was diagnosed in 18 (66%) patients, 4 (22.2%) of these presented with sepsis. Average stone burden was 9.2mm (±5.8mm). Of the obstructing stones, 13 (72%) were in the kidney. All patients with an obstructing stone underwent surgical management with retrograde endoscopic approach. Metabolic 24-h-urine analysis was completed in 24 (89%) patients. 17 (62%) had an elevated urine density, 15 (55%) demonstrated calcium oxalate supersaturation, 12 (44%) met criteria for acidosis, and 7 (26%) had significant hypocitraturia. NVNA patients represent a unique cohort whose clinical presentation is atypical. Limited ability to express symptoms makes early detection difficult to recognize. Twenty two percent of patients present with sepsis as their first manifestation of an acutely obstructing kidney stone. Pain is subjectively interpreted by caregivers and is an uncommon symptom. Our cohort demonstrates common risk factors for stones including propensity for chronic dehydration, slow urinary tract transit, ineffective bladder emptying, G-tube feeding, and lithogenic medications. NVNA pediatric patients have atypical kidney stone clinical presentation. Awareness of this unique group of patients should support future collaborative studies to focus on understanding these atypical presentations and reflect on improving management.

Coexistence of acute pancreatitis and an obstructing upper ureteral calculus: does a calculus cause pancreatitis? a case report.

A 36-year-old male patient presented with epigastric, and right loin pain with decreased urine output for 3 days. On physical examination, he had central abdominal and right flank tenderness. An abdominal ultrasound showed mild to moderate ascites, a hyperechoic pancreas, a small (26×77mm) left kidney with increased echogenicity, right renal hypertrophy with moderate hydronephrosis, and a dilated upper ureter due to a 10mm obstructing stone with a perirenal fluid collection. The diagnosis of acute pancreatitis with an obstructing right upper ureteric stone was established. Under spinal anesthesia, an emergency ureteroscopy with laser fragmentation of the stone was performed, and a JJ stent was inserted. He developed postobstructive diuresis and his renal function was improved with a rapid decline of pancreatic enzymes as well. Two theories explain the presentation of acute pancreatitis by ureteral obstruction. First, the obstructed severe hydronephrotic kidney compresses the duodenum and head of the pancreas, obstructing the distal part of the common bile duct and triggering the elevation of pancreatic duct pressure, bile reflux, trypsin activation, and pancreatic autodigestion. The second theory states that acute pancreatitis develops when urine is extravasated from an obstructed kidney into the adjacent tissues, irritating the uncinate process of the pancreas. Although mentioning ureteral obstruction as a cause of pancreatitis is scarce, the clinician should be aware that in each case of ureteral obstruction, the emergence of acute pancreatitis is a possible complication.

BET Protein Inhibitor JQ1 Modulates Mitochondrial Dysfunction and Oxidative Stress Induced by Chronic Kidney Disease.

Among the mechanisms involved in the progression of kidney disease, mitochondrial dysfunction has special relevance. Epigenetic drugs such as inhibitors of extra-terminal domain proteins (iBET) have shown beneficial effects in experimental kidney disease, mainly by inhibiting proliferative and inflammatory responses. The impact of iBET on mitochondrial damage was explored in in vitro studies in renal cells stimulated with TGF-β1 and in vivo in murine unilateral ureteral obstruction (UUO) model of progressive kidney damage. In vitro, JQ1 pretreatment prevented the TGF-β1-induced downregulation of components of the oxidative phosphorylation chain (OXPHOS), such as cytochrome C and CV-ATP5a in human proximal tubular cells. In addition, JQ1 also prevented the altered mitochondrial dynamics by avoiding the increase in the DRP-1 fission factor. In UUO model, renal gene expression levels of cytochrome C and CV-ATP5a as well as protein levels of cytochrome C were reduced These changes were prevented by JQ1 administration. In addition, JQ1 decreased protein levels of the DRP1 fission protein and increased the OPA-1 fusion protein, restoring mitochondrial dynamics. Mitochondria also participate in the maintenance of redox balance. JQ1 restored the gene expression of antioxidant proteins, such as Catalase and Heme oxygenase 1 in TGF-β1-stimulated human proximal tubular cells and in murine obstructed kidneys. Indeed, in tubular cells, JQ1 decreased ROS production induced by stimulation with TGF-β1, as evaluated by MitoSOXTM. iBETs, such as JQ1, improve mitochondrial dynamics, functionality, and oxidative stress in kidney disease.

JMJD3 Promotes Myeloid Fibroblast Activation and Macrophage Polarization in Kidney Fibrosis.

Renal fibrosis is a common feature of chronic kidney disease. Myeloid fibroblasts and macrophages contribute significantly to the pathogenesis of renal fibrosis. However, the molecular mechanisms underlying myeloid fibroblast activation and macrophage polarization are not fully understood. In this study, we examined the role of JMJD3 in myeloid fibroblast activation, macrophage polarization, and renal fibrosis development in a preclinical model of obstructive nephropathy. To examine the role of JMJD3 in renal fibrosis, we generated mice with global or myeloid cell-specific deletion of JMJD3, and we treated wild-type mice with vehicle or GSK-J4, a selective JMJD3 inhibitor. Mice were subjected to unilateral ureteral obstructive injury to induced renal fibrosis. JMJD3 expression was significantly increased in the kidneys during the development of renal fibrosis, which was associated with an increase in H3K27 dimethylation. Mice with global or myeloid JMJD3 deficiency exhibited significantly reduced total collagen deposition and extracellular matrix protein production, myeloid fibroblast activation, and M2 macrophage polarization in the obstructed kidney. Moreover, IFN regulatory factor 4, a mediator of M2 macrophage polarization, was significantly induced in the obstructed kidneys, which was abolished by JMJD3 deficiency. Furthermore, pharmacological inhibition of JMJD3 with GSK-J4 attenuated kidney fibrosis, reduced myeloid fibroblast activation, and suppressed M2 macrophage polarization in the obstructed kidney. Our study identifies JMJD3 as a critical regulator of myeloid fibroblast activation, macrophage polarization, and renal fibrosis development. Therefore, JMJD3 may represent a promising therapeutic target for chronic kidney disease.

Low dose Taxol ameliorated renal fibrosis in mice with diabetic kidney disease by downregulation of HIPK2.

Our previous studies reported that low-dose paclitaxel (Taxol) ameliorated renal fibrosis in the unilateral ureteral obstruction and remnant kidney models. However, the regulatory role of Taxol in diabetic kidney disease (DKD) is still unclear. Herein, we observed that low-dose Taxol attenuated high glucose-increased expression of fibronectin, collagen I and collagen IV in Boston University mouse proximal tubule cells. Mechanistically, Taxol suppressed the expression of homeodomain-interacting protein kinase 2 (HIPK2) via disrupting the binding of Smad3 to HIPK2 promoter region, and consequently inhibited the activation of p53. Besides, Taxol ameliorated RF in Streptozotocin mice and db/db-induced DKD via suppression of Smad3/HIPK2 axis as well as inactivation of p53. Altogether, these results suggest that Taxol can block Smad3-HIPK2/p53 axis, thereby attenuating the progression of DKD. Hence, Taxol is a promising therapeutic drug for DKD.