Long non-coding RNA FABP5P3/miR-22 axis improves TGFß1-induced fatty acid oxidation deregulation and fibrotic changes in proximal tubular epithelial cells of renal fibrosis.

Severe hydronephrosis increases the risk of urinary tract infection and irretrievable renal fibrosis. While TGFß1-mediated fibrotic changes in proximal tubular epithelial cells and fatty acid oxidation (FAO) deregulation contribute to renal fibrosis and hydronephrosis. Firstly, a few elements were analyzed in this paper, including differentially-expressed long non-coding RNAs (lncRNAs), and miRNAs correlated to CPT1A, RXRA, and NCOA1. This paper investigated TGFß1 effects on lncRNA FABP5P3, CPT1A, RXRA, and NCOA1 expression and fibrotic changes in HK-2 cells and FABP5P3 overexpression effects on TGFß1-induced changes. Moreover, this paper predicted and proved that miR-22 binding to lncRNA FABP5P3, 3'UTR of CPT1A, RXRA, and NCOA1 was validated. The dynamic effects of the FABP5P3/miR-22 axis on TGFß1-induced changes were investigated. A Renal fibrosis model was established in unilateral ureteral obstruction (UUO) mice, and FABP5P3 effects were investigated. Eventually, this paper concluded that TGFß1 inhibited lncRNA FABP5P3, CPT1A, RXRA, and NCOA1 expression, induced fibrotic changes in HK-2 cells, and induced metabolic reprogramming within HK-2 cells, especially lower FAO. FABP5P3 overexpression partially reversed TGFß1-induced changes. miR-22 targeted lncRNA FABP5P3, CPT1A, RXRA, and NCOA1. LncRNA FABP5P3 counteracted miR-22 inhibition of CPT1A, NCOA1, and RXRA through competitive binding. TGFß1 stimulation induced the activation of TGFß/SMAD and JAG/Notch signaling pathways; Nocth2 knockdown reversed TGFß1 suppression on lncRNA FABP5P3. FABP5P3 overexpression attenuated renal fibrosis in unilateral ureteral obstruction mice. The LncRNA FABP5P3/miR-22 axis might be a potent target for improving the FAO deregulation and fibrotic changes in proximal TECs under TGFß1 stimulation.

Consistent alteration of chain length-specific ceramides in human and mouse fibrotic kidneys.

BACKGROUND: Several studies revealed alterations of single sphingolipid species, such as chain length-specific ceramides, in plasma and serum of patients with kidney diseases. Here, we investigated whether such alterations occur in kidney tissue from patients and mice suffering from renal fibrosis, the common endpoint of chronic kidney diseases. METHODS: Human fibrotic kidney samples were collected from nephrectomy specimens with hydronephrosis and/or pyelonephritis. Healthy parts from tumor nephrectomies served as nonfibrotic controls. Mouse fibrotic kidney samples were collected from male C57BL/6J mice treated with an adenine-rich diet for 14 days or were subjected to 7 days of unilateral ureteral obstruction (UUO). Kidneys of untreated mice and contralateral kidneys (UUO) served as respective controls. Sphingolipid levels were detected by LC-MS/MS. Fibrotic markers were analyzed by TaqMan® analysis and immunohistology. RESULTS: Very long-chain ceramides Cer d18:1/24:0 and Cer d18:1/24:1 were significantly downregulated in both fibrotic human kidney cortex and fibrotic murine kidney compared to respective control samples. These effects correlate with upregulation of COL1α1, COL3α1 and αSMA expression in fibrotic human kidney cortex and fibrotic mouse kidney. CONCLUSION: We have shown that very long-chain ceramides Cer d18:1/24:0 and Cer d18:1/24:1 are consistently downregulated in fibrotic kidney samples from human and mouse. Our findings support the use of in vivo murine models as appropriate translational means to understand the involvement of ceramides in human kidney diseases. In addition, our study raises interesting questions about the possible manipulation of ceramide metabolism to prevent progression of fibrosis and the use of ceramides as potential biomarkers of chronic kidney disease.

Quantitative Proteome of Infant Stenotic Ureters Reveals Extracellular Matrix Organization and Oxidative Stress Dysregulation Underlying Ureteropelvic Junction Obstruction.

PURPOSE: Ureteropelvic junction obstruction (UPJO) is the most frequent cause of congenital hydronephrosis in child. To better investigate the molecular mechanisms of this pathological process, the stenotic ureter proteome of UPJO in infants is compared with their own normal pre-stenotic segments. EXPERIMENTAL DESIGN: Data independent acquisition-based proteomics are performed to compare proteome between pre-stenotic and stenotic ureter from nine UPJO infants. Gene ontology analysis, hierarchical cluster analysis, and network interaction are performed to characterize biological functions of significantly altered proteins. Selected significantly altered proteins are validated by western blot on another three UPJO infants. RESULTS: 15 proteins are up-regulated and 33 proteins are down-regulated during stenotic pathology. Significantly altered proteins are involved in decreased extracellular matrix and cytoskeleton organization, increased regulation of oxidative activity, and altered inflammatory associated exocytosis. Significant expression of biglycan, fibulin-1, myosin-10, cytochrome b5 are validated providing possible mechanism in UPJO which could be associated impaired smooth muscle cell, epithelial integrity, and increased oxidative stress. CONCLUSIONS AND CLINICAL RELEVANCE: This study provides molecular evidence of dysregulated extracellular matrix organization, impaired smooth muscle cell, and oxidative stress during UPJO pathology, indicating that biglycan, fibulin-1, myosin-10, cytochrome b5 might reflect the pathology of UPJO.

Bladder-sparing treatment of nonmetastatic muscle-invasive bladder cancer.

Bladder-sparing therapies for the treatment of nonmetastatic muscle-invasive bladder cancers are included in both American and European guidelines. Numerous treatment approaches have been described, including partial cystectomy, radiation monotherapy, and radical transurethral resection. However, the most oncologically favorable and well-studied regimen employs a multimodal approach that consists of maximal transurethral resection of the bladder tumor followed by concurrent radiosensitizing chemotherapy and radiotherapy. This sequence, referred to as trimodal therapy (TMT), has been evaluated with robust retrospective comparative studies and prospective series, although a randomized trial comparing TMT with radical cystectomy has not been performed. Despite promising reports of 5-year overall survival rates of 50% to 70% in well-selected patients, relatively few patients qualify as ideal candidates for TMT. Specifically, contemporary series exclude patients who have clinical stage T3 disease, multifocal tumors, coexisting carcinoma in situ, or hydronephrosis. Herein, we review all forms of bladder-preserving therapies with an emphasis on TMT, highlighting the rationale of each component, survival outcomes, and future directions.

Connecting Versatile lncRNAs with Heterogeneous Nuclear Ribonucleoprotein K and Pathogenic Disorders.

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA-binding protein that regulates multiple biological processes, including paraspeckles formation and cellular signal transduction. Recently, hnRNPK has been shown to interact with SINE-derived nuclear RNA localization (SIRLOIN)-containing RNAs, and orchestrate nuclear enrichment and cellular functions of long noncoding RNAs (lncRNAs). hnRNPK-lncRNAs interaction is potentially implicated in various pathogenic disorders including tumorigenesis, and Kabuki-like, Au-Kline, and Okamoto syndromes.

Aquaporin1-3 expression in normal and hydronephrotic kidneys in the human fetus.

BACKGROUND: Decreased expression of the renal aquaporin (AQP) protein family is associated with hydronephrosis in adult humans and animals. However, the expression of AQPs, especially subtypes AQP1-3, which play a core role in the urinary concentration function, in hydronephrotic human fetuses is not clear. The aim of this study is to investigate the expression of the AQP1-3 in normal and hydronephrotic human fetal kidneys. METHODS: Twenty-one normal and six hydronephrotic kidney (HK) samples were harvested from abortive fetuses. Meanwhile, seven normal adult human kidney samples were collected as positive controls. Quantitative real-time PCR, western blotting, and immunohistochemistry were used to analyze the expression of AQP1-3. RESULTS: Both the protein and messenger mRNA expression levels of AQP1-3 increased with gestational age in the normal fetuses, but the levels were significantly lower than those in the adult tissues and significantly higher than those in the hydronephrotic fetuses at the same gestational age. CONCLUSIONS: The increased expression of AQP1-3 with gestational age in the fetal kidney may indicate maturation of the urinary concentrating ability. The lower expression of AQP1-3 in HKs may reflect a maturation obstacle with regard to urinary concentration in human hydronephrotic fetuses.

Mechanisms of Developmental Toxicity of Dioxins and Related Compounds.

Dioxins and related compounds induce morphological abnormalities in developing animals in an aryl hydrocarbon receptor (AhR)-dependent manner. Here we review the studies in which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is used as a prototypical compound to elucidate the pathogenesis of morphological abnormalities. TCDD-induced cleft palate in fetal mice involves a delay in palatogenesis and dissociation of fused palate shelves. TCDD-induced hydronephrosis, once considered to be caused by the anatomical obstruction of the ureter, is now separated into TCDD-induced obstructive and non-obstructive hydronephrosis, which develops during fetal and neonatal periods, respectively. In the latter, a prostaglandin E2 synthesis pathway and urine concentration system are involved. TCDD-induced abnormal development of prostate involves agenesis of the ventral lobe. A suggested mechanism is that AhR activation in the urogenital sinus mesenchyme by TCDD modulates the wingless-type MMTV integration site family (WNT)/ß-catenin signaling cascade to interfere with budding from urogenital sinus epithelium. TCDD exposure to zebrafish embryos induces loss of epicardium progenitor cells and heart malformation. AHR2-dependent downregulation of Sox9b expression in cardiomyocytes is a suggested underlying mechanism. TCDD-induced craniofacial malformation in zebrafish is considered to result from the AHR2-dependent reduction in SRY-box 9b (SOX9b), probably partly via the noncoding RNA slincR, resulting in the underdevelopment of chondrocytes and cartilage.

THE ROLE OF RADIOACTIVE METHODS IN THE DIAGNOSTIC TYPE OF HYDRONEPHROSIS IN CLEAN-UP WORKERS OF CHORNOBYL ACCIDENT. / ROL' RADIONUKLIDNYKh METODIV V DIAGNOSTYChNII TAKTYTsI GIDRONEFROZU V UChASNYKIV LIKVIDATsIÏ NASLIDKIV AVARIÏ NA ChORNOBYL'S'KII ATOMNII ELEKTROSTANTsIÏ.

RATIONALE: Since the introduction of radionuclide research methods into clinical practice, they occupy an importantplace in the diagnosis of hydronephrosis and, at the same time, sufficiently objective, sensitive and atraumaticmethods of investigation. OBJECTIVE: On the basis of retrospective data, to investigate the diagnostic role of radionuclide renography (RRG)and the method of indirect radionuclide renangiography (IRAG) in clean-up workers of Chornobyl accident withhydronephrosis. MATERIALS AND METHODS: A total of 257 patients with hydronephrosis (140 women and 117 men) aged 15 to 77 yearswere examined by the RRG and the IRAG. The RRG technique consists of intravenous administration of a solution of131I-hypurane (2.5 kBq/kg) and continuous registration for 20 minutes of the level of radioactivity above the kid-neys with the help of sensors of the renograph UR 1-1. The IRAG was conducted for 30-45 seconds with exposure1 frame per second after intravenous administration of a solution of 99mTc-pentatech (2 MBq/kg). RESULTS: The results of the radionuclide study of the hemodynamics of patients with different stages ofhydronephrosis made it possible to draw a conclusion regarding the expediency of taking into account the condi-tion of the cup-pelvic system in the preoperative period, as well as the parameters of the arterial and venous circu-lation. CONCLUSIONS: Combined use of X-ray and radionuclide methods allows establishing the cause and consequences ofhydronephrosis, to develop a rational treatment plan. RRG and IRAG are reliable methods of dynamic control in post-operative observation of clean-up workers of Chornobyl accident with hydronephrosis.

Changes in cell fate determine the regenerative and functional capacity of the developing kidney before and after release of obstruction.

Congenital obstructive nephropathy is a major cause of chronic kidney disease (CKD) in children. The contribution of changes in the identity of renal cells to the pathology of obstructive nephropathy is poorly understood. Using a partial unilateral ureteral obstruction (pUUO) model in genetically modified neonatal mice, we traced the fate of cells derived from the renal stroma, cap mesenchyme, ureteric bud (UB) epithelium, and podocytes using Foxd1Cre, Six2Cre, HoxB7Cre, and Podocyte.Cre mice respectively, crossed with double fluorescent reporter (membrane-targetted tandem dimer Tomato (mT)/membrane-targetted GFP (mG)) mice. Persistent obstruction leads to a significant loss of tubular epithelium, rarefaction of the renal vasculature, and decreased renal blood flow (RBF). In addition, Forkhead Box D1 (Foxd1)-derived pericytes significantly expanded in the interstitial space, acquiring a myofibroblast phenotype. Degeneration of Sine Oculis Homeobox Homolog 2 (Six2) and HoxB7-derived cells resulted in significant loss of glomeruli, nephron tubules, and collecting ducts. Surgical release of obstruction resulted in striking regeneration of tubules, arterioles, interstitium accompanied by an increase in blood flow to the level of sham animals. Contralateral kidneys with remarkable compensatory response to kidney injury showed an increase in density of arteriolar branches. Deciphering the mechanisms involved in kidney repair and regeneration post relief of obstruction has potential therapeutic implications for infants and children and the growing number of adults suffering from CKD.

Oxidative damage and mitochondrial injuries differ following pneumoperitoneum pressure in rabbit models of varying degrees of hydronephrosis.

The influence of intraabdominal pressure which is necessary to maintain the operating area during the surgery cannot be ignored especially on the kidneys. Many articles have reported the effect of intraabdominal pressure on normal kidneys. However, the influence of intraabdominal pressure on hydronephrosis kidneys is rarely studied. The aim of the present study was to clarify whether intraabdominal pressure tolerance is modified in various degrees of kidney hydronephrosis by evaluating oxidative damage and mitochondrial injuries. A total of 72 rabbits were randomly divided into three groups (groups N, M and S, which represented rabbits with no, mild and severe hydronephrosis, respectively). Rabbits in groups M (n=24) and S (n=24) underwent a surgical procedure inducing mild or severe hydronephrosis, respectively. Subsequently, rabbits in all groups were allocated to 4 subgroups (N0­N3, M0­M3 and S0­S3) consisting of 6 rabbits each. Groups 0 to 3 were, respectively, subjected to intraabdominal pressures of 0, 5, 10 and 15 mmHg. Oxidative damage was assessed by analyzing levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH­Px), catalase (CAT) and lactate (LD). Mitochondrial injuries were assessed based on mitochondrial membrane potential (MMP) alterations, mitochondrial structure and cytochrome c (cytc) protein expression, as measured by JC­1 staining, electron microscopy and western blotting, respectively. Oxidative damage and mitochondrial injuries were noticeably exacerbated in group N and M with increased levels of ROS, MDA and LD, decreased levels of SOD, GSH­Px, CAT and MMP, mitochondrial vacuolization and higher expression of cytc when the intraabdominal pressure reached 15 mmHg. In group S, these alterations occurred at pressures of 10 and 15 mmHg. Therefore, it was concluded that in rabbits exposed to pneumoperitoneal pressure, kidneys with severe hydronephrosis were more likely to suffer from oxidative damage and mitochondrial injuries compared with kidneys with mild hydronephrosis and normal kidneys.

The molecular biology of pelvi-ureteric junction obstruction.

Over recent years routine ultrasound scanning has identified increasing numbers of neonates as having hydronephrosis and pelvi-ureteric junction obstruction (PUJO). This patient group presents a diagnostic and management challenge for paediatric nephrologists and urologists. In this review we consider the known molecular mechanisms underpinning PUJO and review the potential of utilising this information to develop novel therapeutics and diagnostic biomarkers to improve the care of children with this disorder.

Semaphorin-3A and Netrin-1 predict the development of kidney injury in children with congenital hydronephrosis.

Congenital obstructive nephropathy is amongst the main causes of chronic renal failure in children. Early diagnosis and initiation of the treatment will delay progressive renal tubular atrophy and interstitial fibrosis with the loss of nephrons. The aim of this study was to evaluate whether urinary (u) semaphorin-3A (SEMA-3A) and Netrin-1 may be potential biomarkers in children with congenital hydronephrosis due to ureteropelvic junction obstruction (UPJO). The study consisted of 42 children with severe hydronephrosis who needed surgery and two control groups (Control One: 42 children with mild, non-obstructive hydronephrosis; Control Two: 44 healthy children). All children had normal renal function. Urinary semaphorin-3A and Netrin-1 levels were measured in different groups using immunoenzymatic ELISA commercial kits. Compared with Control One and Control Two groups, the preoperative median uSEMA-3A/creatinine (cr.) and uNetrin-1/cr. levels increased significantly in the children with severe hydronephrosis (p < .01). One month after surgery, uSEMA-3A/cr. and uNetrin-1/cr. levels had decreased significantly in the children with severe hydronephrosis (p < .01), but were still higher than those in both control groups (p < .05). Receiver operator characteristic (ROC) analyses revealed a good diagnostic profile for uSEMA-3A and uNetrin-1 in terms of identifying children with a differential renal function of <40% [area under the curve (AUC) 0.825 and 0.745, respectively]. Our results indicate that increased concentrations of uSEMA-3A and uNetrin-1 are found in urine from children with severe hydronephrosis and that their concentrations are related to the degree of obstruction.

Urinary bladder hypertrophy characteristic of male ROMK Bartter's mice does not occur in female mice.

The renal outer medullary potassium channel (ROMK; Kir1.1) plays an important role in Na+ and K+ homeostasis. ROMK knockout (KO) mice show a similar phenotype to Bartter's syndrome of salt wasting and dehydration due to reduced Na-2Cl-K-cotransporter activity but not in ROMK1 KO mice. ROMK KO mice also show hydronephrosis; however, the mechanism of this phenotype has not been understood. We have previously demonstrated a gender-sex difference in hydronephrosis and PGE2 production in ROMK KO mice. In this study we compared the gender-sex difference in bladder hypertrophy and hydronephrosis in ROMK KO mice. The bladder weight, bladder capacity, and the thickness of urothelium in male ROMK KO showed average increased two to approximately fourfold greater than wild-type (WT) mice, but there was no difference in either female or ROMK1 KO mice. The thickness of the urothelium was 648.8 ± 33.2 µm vs. 302.7 ± 16.5 µm ( P < 0.001) and the detrusor muscle 1,940.7 ± 98.9 µm vs. 1,308.2 ± 102.1 µm ( P = 0.013), respectively, in 12-mo male ROMK KO mice compared with the same age WT mice. Western blotting detected ROMK expression at 45~48 kDa, and both ROMK1 and ROMK2 mRNA were detected by quantitative PCR in the bladder. Immunofluorescence staining showed ROMK stained in the bladder, ureter, and urethra in WT but not in KO. In addition, there was a correlation between the severity of hydronephrosis and the bladder weight in male but not in female ROMK KO mice. In conclusion, ROMK expressed in the urinary tract at both protein and mRNA levels; significant enlargement and hypertrophy of the bladder may contribute to hydronephrosis in male ROMK KO mice.

Constitutive Activation of Smoothened in the Renal Collecting Ducts Leads to Renal Hypoplasia, Hydronephrosis, and Hydroureter.

Sonic Hedgehog (Shh) signaling plays a major role in and is essential for regulation, patterning, and proliferation during renal development. Smoothened (Smo) plays a pivot role in transducing the Shh-glioma-associated oncogene Kruppel family member. However, the cellular and molecular mechanism underlying the role of sustained Smo activation in postnatal kidney development is still not clearly understood. Using a conditional knockin mouse model that expresses a constitutively activated form of Smo (SmoM2) upon Homeobox-B7-mediated recombination (Hoxb7-Cre), the effects of Shh signaling were determined in postnatal kidney development. SmoM2;Hoxb7-Cre mutant mice showed growth retardation with a reduction of body weight. Constitutive activation of Smo in the renal collecting ducts caused renal hypoplasia, hydronephrosis, and hydroureter. The parenchymal area and glomerular numbers were reduced, but the glomerular density was increased in SmoM2;Hoxb7-Cre mutant mice. The expression of Patched 1, the receptor of Shh and a downstream target gene of the Shh signaling pathway, was highly restricted and it was upregulated in the inner medullary collecting ducts of the kidney. The proliferative cells in the mesenchyme and collecting ducts were decreased in SmoM2;Hoxb7-Cre mutant mice. This study showed for the first time that sustained Smo inhibits postnatal kidney development by suppressing the proliferation of the mesenchyme and medullary collecting ducts in mice.

Forming a stone in pelviureteric junction obstruction: cause or effect?

ABSTRACT Objectives To investigate a possible causal relationship for stone formation in pelviureteric junction obstruction and to outline management options. Materials and Methods A literature search and evidence synthesis was conducted via electronic databases in the English language using the key words pelviureteric junction obstruction; urolithiasis; hyperoxaluria; laparoscopic pyeloplasty; flexible nephroscopy; percutaneous nephrolithotomy, alone or in combination. Relevant articles were analysed to extract conclusions. Results Concomitant pelviureteric junction obstruction (PUJO) and renal lithiasis has been reported only scarcely in the literature. Although PUJO has been extensively studied throughout the years, the presence of calculi in such a patient has not received equal attention and there is still doubt surrounding the pathophysiology and global management. Conclusions Metabolic risk factors appear to play an important role, enough to justify metabolic evaluation in these patients. Urinary stasis and infection are well known factors predisposing to lithiasis and contribute to some extent. The choice for treatment is not always straightforward. Management should be tailored according to degree of obstruction, renal function, patient symptoms and stone size. Simultaneous treatment is feasible with the aid of minimally invasive operative techniques and laparoscopy in particular.

Forming a stone in pelviureteric junction obstruction: Cause or effect?

OBJECTIVES: To investigate a possible causal relationship for stone formation in pelviureteric junction obstruction and to outline management options. MATERIALS AND METHODS: A literature search and evidence synthesis was conducted via electronic databases in the English language using the key words pelviureteric junction obstruction; urolithiasis; hyperoxaluria; laparoscopic pyeloplasty; flexible nephroscopy; percutaneous nephrolithotomy, alone or in combination. Relevant articles were analysed to extract conclusions. RESULTS: Concomitant pelviureteric junction obstruction (PUJO) and renal lithiasis has been reported only scarcely in the literature. Although PUJO has been extensively studied throughout the years, the presence of calculi in such a patient has not received equal attention and there is still doubt surrounding the pathophysiology and global management. CONCLUSIONS: Metabolic risk factors appear to play an important role, enough to justify metabolic evaluation in these patients. Urinary stasis and infection are well known factors predisposing to lithiasis and contribute to some extent. The choice for treatment is not always straightforward. Management should be tailored according to degree of obstruction, renal function, patient symptoms and stone size. Simultaneous treatment is feasible with the aid of minimally invasive operative techniques and laparoscopy in particular.

Interobserver agreement on cortical tracer transit in 99mTc-MAG3 renography applied to congenital hydronephrosis.

OBJECTIVE: This study aims to evaluate interobserver agreement on visual analysis of technetium-99m mercaptoacetyltriglycine (Tc-MAG3) renal tissue transit used for the evaluation of antenatal hydronephrosis. MATERIALS AND METHODS: Thirty-eight Tc-MAG3 diuretic renograms were retrospectively collected between 1 and 31 December 2015. The 1-min reframed images were presented to four nuclear medicine consultants and to two nuclear medicine residents, one in the first year of the training program and the others in their fourth and final year. These observers were asked to classify the radiotracer cortical transit (normal/delayed) based solely on visual assessment of the images. For the interobserver agreement, modified Fleiss' kappa (κ) analysis for multiple raters was carried out. For both groups, percentages of agreement were also calculated. RESULTS: A total of 69 kidneys were evaluated. All four nuclear medicine consultants agreed on the classification of 88.4% of the kidneys. When the agreement of at least three of the four observers was considered, the percentage of agreement reached 98.6%. The two nuclear medicine residents agreed on the classification of 69.6% of the kidneys. The modified Fleiss' κ-value was 0.88 (95% confidence interval: 0.79-0.95) for the group of nuclear medicine consultants, indicating almost perfect agreement. For the residents, it was 0.39 (95% confidence interval: 0.16-0.59), suggesting fair agreement. CONCLUSION: Our results seem to indicate that there is an almost perfect agreement in the qualitative identification of delayed cortical transit among physicians with experience at observing renographic images.

Factores predictores de la evolución en la hidronefrosis prenatal / Predictive factors of the outcomes of prenatal hydronephrosis

OBJETIVO: Determinar predictores independientes prenatales y postnatales de una mala evolución de la función renal, de la resolución espontanea o de la necesidad de cirugía en la hidronefrosis prenatal. MÉTODOS: Estudio retrospectivo en pacientes con hidronefrosis prenatal. Analizamos diferentes variables clínicas prenatales y postnatales, así como, el DAP (diámetro anteroposterior) de la pelvis renal en la ecografía prenatal del tercer trimestre, y en la primera y segunda ecografía postnatal. Las analizamos mediante t de Student, chi-cuadrado, análisis de supervivencia, y curvas de COR. RESULTADOS: Se incluyeron 218 pacientes con 293 UR (unidades renales). Operadas 147/293 (50,2%) UR, resolución espontánea 76/293 (25,9%) UR, y 76/293 (25,9%) UR presentaron mala evolución. Encontramos como factores de riesgo para la cirugía el bajo peso al nacer (OR 3,84; IC 95% 1,24-11,84), la prematuridad (OR; 4,17 IC 95% 1,35-12,88), la duplicidad (OR 4,99; IC 95% 2,21-11,23) y la presencia de patología nefrourológica subyacente (OR 53,54; IC 95% 26,23-109,27). Para la no resolución espontánea se encontraron las alteraciones en el volumen del líquido amniótico (RR 1,46; IC 95% 1,33-1,60) así como la patología nefrourológica subyacente y la duplicidad. Para la mala evolución la alteración del volumen del líquido amniótico (OR 11,99; IC 95% 2,70-53,21), la presencia de patología nefrourológica subyacente (OR 4,81 IC 95% 2,60-8,89) y la cirugía (OR 4,23 IC 95% 2,35-7,60). El DAP en las tres ecografías es fiable para la predicción de cirugía (área bajo la curva 0,65; 0,82; 0,71), para resolución espontánea (área bajo la curva 0,80; 0,91; 0,80) y solo el DAP de la primera ecografía postnatal para mala evolución (área bajo la curva 0,73). Los DAP con mayor sensibilidad y especificidad son los de la primera ecografía postnatal; 14,60mm para cirugía; 11,35mm para resolución espontánea; y 15,50 mm para mala evolución. CONCLUSIÓN: A mayor DAP en la pelvis renal en cualquiera de las tres ecografías las probabilidades de cirugía y de no resolución espontanea son mayores. La primera ecografía es la más fiable para predecir la evolución en la hidronefrosis prenatal. Existen otros factores a tomar en cuenta para predecir la evolución de los pacientes con HN prenatal

OBJECTIVES: To determine prenatal and postnatal independent predictors of poor outcome, spontaneous resolution, or the need for surgery in patients with prenatal hydronephrosis. METHODS: We performed a retrospective study of patients with prenatal hydronephrosis. The renal pelvis APD was measured in the third prenatal trimester ultrasound, as well as in the first and second postnatal ultrasound. Other variables were taken into account, both prenatal and postnatal. For statistical analysis we used Student t-test, chi-square test, survival analysis, logrank test, and ROC curves. RESULTS: We included 218 patients with 293 renal units (RU). Of these, 147/293 (50.2%) RU were operated. 76/293 (25.9%) RU had spontaneous resolution and other 76/293 (25.9%) RU had poor outcome. As risk factors for surgery we found low birth weight (OR 3.84; 95% CI 1.24-11.84), prematurity (OR 4.17; 95% CI 1.35-12.88), duplication (OR 4.99; 95% CI 2.21- 11.23) and the presence of nephrourological underlying pathology (OR 53.54; 95% CI 26.23-109.27). For the non-spontaneous resolution, we found as risk factors the alterations of amniotic fluid volume (RR 1.46; 95% CI 1.33-1.60) as well as the underlying nephrourological pathology and duplication. In the poor outcome, we found as risk factors the alterations of amniotic fluid volume (OR 4.54; 95% CI 1.31-15.62), the presence of nephrourological pathology (OR 4.81 95% CI 2.60-8.89) and RU that was operated (OR 4.23, 95% CI 2.35-7.60). The APD of the renal pelvis in all three ultrasounds were reliable for surgery prediction (area under the curve 0.65; 0.82; 0.71) or spontaneous resolution (area under the curve 0.80; 0.91; 0.80), only the first postnatal ultrasound has predictive value in the poor outcome (area under the curve 0.73). The higher sensitivity and specificity of the APD as predictor value was on the first postnatal ultrasound, 14.60 mm for surgery; 11.35 mm for spontaneous resolution and 15.50 mm for poor outcome. CONCLUSION: The higher APD in the renal pelvis in any of the three ultrasounds, the greater the chances of surgery and failure of spontaneous resolution. The first postnatal ultrasound is the most reliable in predicting outcome of prenatal hydronephrosis. There are other factors to take into account to predict the outcomes of these patients

ATP5B and ETFB metabolic markers in children with congenital hydronephrosis.

Congenital obstructive nephropathy is the primary cause of chronic renal failure in children. Disorders of mitochondrial energy metabolism may be a primary factor underlying tubular cell apoptosis in hydronephrosis. The ß-F1-ATPase (ATP5B) and electron transfer flavoprotein ß subunit (ETFB) metabolic markers are involved in mitochondrial energy metabolism in other diseases. The aim of the present study was to evaluate whether ATP5B and ETFB are represented in the hydronephrotic kidney, and whether they are associated with the progression of hydronephrosis. The cohort examined consisted of 20 children with hydronephrosis, graded III and IV using the Society for Fetal Urology grading system, and a control group consisting of 20 patients with nephroblastoma. Reverse transcription­quantitative polymerase chain reaction and immunoblot analyses were used to investigate the differential expression of genes and proteins in the two groups. The gene and protein expression levels of ATP5B and ETFB were upregulated in the hydronephrosis group. Correlation analyses revealed negative correlations between ATP5B, ETFB protein and split renal function (SRF). Receiver­operator curve analysis found a diagnostic profile of the ETFB protein in identifying children with hydronephrosis with abnormal SRF (<45%). These results suggested that increasing levels of ATP5B and ETFB were associated with worsening renal injury. ATP5B and ETFB may be novel markers in hydronephrosis and require further detailed investigation.

Kidney epithelium specific deletion of kelch-like ECH-associated protein 1 (Keap1) causes hydronephrosis in mice.

BACKGROUND: Transcription factor Nrf2 protects from experimental acute kidney injury (AKI) and is promising to limit progression in human chronic kidney disease (CKD) by upregulating multiple antioxidant genes. We recently demonstrated that deletion of Keap1, the endogenous inhibitor of Nrf2, in T lymphocytes significantly protects from AKI. In this study, we investigated the effect of Keap1 deletion on Nrf2 mediated antioxidant response in the renal tubular epithelial cells. METHODS: We deleted Keap1 exon 2 and 3 in the renal tubular epithelial cells by crossing Ksp-Cre mice with Keap1 floxed (Keap1 (f/f)) mice. Deletion of Keap1 gene in the kidney epithelial cells of Ksp-Keap1 (-/-) mice and its effect on Nrf2 target gene expression was performed using PCR and real-time PCR respectively. Histological evaluation was performed on H&E stained sections. Complete blood count, serum and urine analysis were performed to assess systemic effects of defective kidney development. Student's T test was used to determine statistical difference between the groups. RESULTS: Ksp-Cre resulted in the deletion of Keap1 exon 2 and 3 and subsequent upregulation of Nrf2 target genes, Nqo1, Gclm and Gclc in the kidney epithelial cells of Ksp-Keap1 (-/-) mice at baseline. Renal epithelial cell specific deletion of Keap1 in Ksp-Keap1 (-/-) mice caused marked renal pelvic expansion and significant compression of medullary parenchyma consistent with hydronephrosis in both (3 month-old) males and females. Kidneys from 6 month-old Ksp-Keap1 (-/-) mice showed progressive hydronephrosis. Hematological, biochemical and urinary analysis showed significantly higher red blood cell count (p = 0.04), hemoglobin (p = 0.01), hematocrit (p = 0.02), mean cell volume (p = 0.02) and mean cell hemoglobin concentration (p = 0.003) in Ksp-Keap1 (-/-) mice in comparison to Keap1 (f/f) mice. CONCLUSIONS: These unexpected findings demonstrate that Keap1 deletion in renal tubular epithelial cells results in an abnormal kidney development consistent with hydronephrosis and reveals a novel Keap1 mediated signaling pathway in renal development.