Long noncoding RNAs may impact podocytes and proximal tubule function through modulating miRNAs expression in Early Diabetic Kidney Disease of Type 2 Diabetes Mellitus patients.

Aims: Long noncoding RNAs (lncRNAs) play key roles in the pathophysiology of DKD involving actions of microRNAs (miRNAs). The aims of the study were to establish the involvement of selected lncRNAs in the epigenetic mechanisms of podocyte damage and tubular injury in DKD of type 2 diabetes mellitus (DM) patients in relation to a particular miRNAs profile. Methods: A total of 136 patients with type 2 DM and 25 healthy subjects were assessed in a cross-sectional study concerning urinary albumin: creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (synaptopodin, podocalyxin) and of proximal tubule (PT) dysfunction (Kidney injury molecule-1-KIM-1, N-acetyl-D-glucosaminidase-NAG), urinary lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), nuclear-enriched abundant transcript 1 (NEAT1), myocardial infarction-associated transcript (MIAT), taurine-upregulated gene 1 (TUG1), urinary miRNA21, 124, 93, 29a. Results: Multivariable regression analysis showed that urinary lncMALAT1 correlated directly with urinary synaptopodin, podocalyxin, KIM-1, NAG, miRNA21, 124, UACR, and negatively with eGFR, miRNA93, 29a (p<0.0001; R2=0.727); urinary lncNEAT1 correlated directly with synaptopodin, KIM-1, NAG, miRNA21, 124, and negatively with eGFR, miRNA93, 29a (p<0.0001; R2=0.702); urinary lncMIAT correlated directly with miRNA93 and 29a, eGFR (p<0.0001; R2=0.671) and negatively with synaptopodin, KIM-1, NAG, UACR, miRNA21, 124 (p<0.0001; R2=0.654); urinary lncTUG1 correlated directly with eGFR, miRNA93, 29a, and negatively with synaptopodin, podocalyxin, NAG, miRNA21, 124 (p<0.0001; R2=0.748). Conclusions: In patients with type 2 DM lncRNAs exert either deleterious or protective functions within glomeruli and PT. LncRNAs may contribute to DKD through modulating miRNAs expression and activities. This observation holds true independently of albuminuria and DKD stage.

Replaced right hepatic artery originated from splenic artery, in association with gastrosplenic trunk: a case report.

The authors report a case of a 74-year-old woman found to have an extremely rare case highlighted by multidetector computed tomography (MDCT) angiography, with the presence of a replaced right hepatic artery (RRHA) arising from the splenic artery (SA). In this case, the SA arose from a gastrosplenic trunk (GST). The GST had an endoluminal diameter of 9.2 mm at its origin and a length of 9.3 mm. It arose directly from the anterior abdominal aortic wall, at the level of the T12-L1 intervertebral disc. The SA branched off from the GST and travelled in front of the abdominal aorta (AA) for 18.2 mm up to the level of the L1-L2 intervertebral disc. The SA then continued along an upward and tortuous path towards the splenic hilum. The inflection point of the SA trunk was located above the origin of superior mesenteric artery (SMA). The RRHA arose from the right of this inflection point. The RRHA had an endoluminal diameter of 3.0 mm at its origin and a length of 96.0 mm; it had a downward trajectory towards the hepatic hilum. The common hepatic artery (CHA) had an endoluminal diameter of 6.2 mm at origin and arose directly from the anterior wall immediately to the right of the mediosagittal plane of the AA. Knowledge of this rare anatomical variation is important for interventional radiologists, oncologists, hepatic and abdominal surgeons.

Pro-inflammatory cytokines are associated with podocyte damage and proximal tubular dysfunction in the early stage of diabetic kidney disease in type 2 diabetes mellitus patients.

AIMS: To evaluate if there is a link between inflammation (expressed by inflammatory cytokines) and the early stage of diabetic kidney disease (DKD), as shown by markers of podocyte damage and proximal tubular (PT) dysfunction. METHODS: In this study were enrolled 117 type 2 DM patients (36-normoalbuminuria, 42-microalbuminuria, 39- macroalbuminuria), and 11 healthy subjects. Serum and urinary IL-1 alpha, IL-8, IL-18, urinary albumin:creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (podocalyxin, synaptopodin, nephrin) and of PT dysfunction (KIM-1, NAG) were assessed. RESULTS: In multivariable regression urinary Il-1 alpha correlated positively with podocalyxin and NAG (p < 0.0001, R2= 0.57); urinary IL-8 correlated directly with synaptopodin, NAG, nephrin, and KIM-1 (p < 0.0001, R2 = 0.67); urinary IL-18 correlated directly with synaptopodin, NAG, and nephrin (p < 0.0001, R2 = 0.59). Serum IL-1 alpha correlated positively with nephrin, synaptopodin, NAG (P < 0.0001, R2 = 0.68); serum IL-8 correlated directly with synaptopodin and NAG (p < 0.0001, R2 = 0.66); serum IL-18 correlated directly with NAG, KIM-1, and podocalyxin (p < 0.0001, R2=0.647). CONCLUSIONS: Pro-inflammatory interleukins are associated with podocyte injury and PT dysfunction in early DKD. These could exert a key role in the pathogenesis of early DKD, before the development of albuminuria.

MiRNA Expression is Associated with Clinical Variables Related to Vascular Remodeling in the Kidney and the Brain in Type 2 Diabetes Mellitus Patients.

Background: The association of vascular remodeling in the kidney and the brain with a particular microRNAs (miRNA) profile is not well studied.Methods: Seventy-six patients with Type 2 diabetes and 11 healthy subjects were assessed concerning urine albumin: creatinine ratio (UACR), biomarkers of podocyte injury and of proximal tubule (PT) dysfunction. MiRNA were quantified in blood and urine by a real-time PCR System. Cerebrovascular ultrasound measurements were performed in the carotid and middle cerebral arteries.Results: MiRNA21 and miRNA124 correlated positively with nephrin, podocalyxin, synaptopodin, urinary N-acetyl-D-glucosaminidase (NAG), urinary kidney-injury molecule-1 (KIM-1), UACR, and negatively with eGFR; miRNA125a, 126, 146a, 192 correlated negatively with nephrin, podocalyxin, synaptopodin, urinary NAG, urinary KIM-1, UACR, and directly with eGFR. Plasma miRNA-21 and miRNA192 correlated directly with cerebral hemodynamics parameters of atherosclerosis and arteriosclerosis. MiRNA-124, 125a, 126, 146a showed negative correlations with the same parameters.Conclusions: In Type 2 diabetes patients there is an association of vascular remodeling in the brain and the kidney with a specific miRNAs pattern. Cerebrovascular changes occur even in normoalbuminuric patients, with 'high-to-normal' levels of podocyte injury and PT dysfunction biomarkers. These phenomena may be explained by the variability of miRNA expression within the two organs in early DKD.

Interleukins and miRNAs intervene in the early stages of diabetic kidney disease in Type 2 diabetes mellitus patients.

Aim: The involvement of proinflammatory interleukins (IL) in diabetic kidney disease of Type 2 diabetes mellitus (DM) patients was studied in relation to a particular miRNA profile. Materials & methods: A total of 117 patients with Type 2 DM and 11 controls were enrolled in a case series study. Serum and urinary ILs and miRNAs were assessed. Results: IL-1α correlated with miRNA21, 124, estimated glomerular filtration rate (eGFR) and negatively with miRNA125a and 192; IL-8 with miRNA21, 124, eGFR and negatively with miRNA125a, 126 and 146a; IL-18 with miRNA21, 124 and negatively with miRNA146a, 192, eGFR. Conclusion: There is an association between specific serum and urinary ILs and serum and urinary miRNAs profiles in the inflammatory response in Type 2 DM patients with diabetic kidney disease.

Rapid decline of kidney function in diabetic kidney disease is associated with high soluble Klotho levels / El rápido deterioro de la función renal en la nefropatía diabética se asocia con niveles elevados de Klotho soluble

BACKGROUND: Klotho is found in two forms: a transmembrane form and a soluble form (s-Klotho). In order to be excreted, s-Klotho, that is too large to be filtered, will probably reach the proximal convoluted tubule by a transcytosis process. The aim of our study was to show the relationship between the levels of s-Klotho and tubular injury in patients with diabetic kidney disease (DKD), using as tubular injury marker the kidney injury molecule-1 (KIM-1). METHODS: Our study included 63 DKD patients (stages 1-5, mean eGFR 65.15 ± 32.45 ml/min) with a mean age 58.13 ± 12 years. In all patients we determined serum levels of: KIM-1 and s-Klotho using ELISA, urinary albumin/creatinine ratio (UACR) and reduction in the estimated glomerular filtration rate (eGFR) per year. RESULTS: We found a strong statistically significant correlation of s-Klotho with the rate of reduction of eGFR/year (r = 0.714, p = 0.0004) and with the tubular injury marker KIM-1 (r = 0.758, p = 0.005) and strong correlations of UACR with the rate of reduction of eGFR/year (r = 0.53, p < 0.01), KIM-1 (r = 0.49, p < 0.05) and s-Klotho (r = 0.52, p < 0.01). CONCLUSION: Despite previous published data, that shows a decrease of s-Klotho in chronic kidney disease, in our study the rapid annual decline of kidney function but not the level of eGFR was associated with increased s-Klotho. A possible explanation could be a more severe proximal tubule injury that could lead to a reduction of tubular excretion of s-Klotho as suggested by the correlation of s-Klotho levels with the serum levels of KIM-1

ANTECEDENTES: Klotho se encuentra en el organismo en dos formas: una forma transmembranaria y una forma soluble (s-Klotho). Para excretarse s-Klotho, que es demasiado grande para ser filtrado, llegará en el túbulo contorneado proximal por un proceso de transcitosis. El objetivo del presente estudio es indicar la relación entre el nivel de s-Klotho y lesión tubular en los pacientes con la enfermedad renal diabética (DKD), utilizando como marcador de lesión tubular renal kidney injury molecule-1 (KIM-1). MÉTODOS: Nuestro estudio incluye 63 pacientes con DKD (etapas 1-5, eGFR medio 65,15 +/− 32,45 ml/min) con una edad media de 58,13 +/− 12 años. En todos los pacientes hemos determinado el nivel sérico de: KIM-1 y s-Klotho utilizando el método ELISA, coeficiente albúmina/creatinina urinaria (UACR) y la reducción de la tasa de filtración glomerular estimada (eGFR) al año. RESULTADOS: Hemos encontrado una correlación fuerte significativa desde el punto de vista estadístico de s-Klotho con una tasa de reducción de eGFR/año (r = 0,714, p = 0,0004) y con el marcador de lesión tubular KIM-1 (r = 0,758, p = 0,005) y una fuerte correlación de UACR con una tasa de reducción de eGFR/año (r = 0,53, p < 0,01), KIM-1 (r = 0,49, p < 0,05) y s-Klotho (r = 0,52, p < 0,01). CONCLUSIONES: A pesar de los datos publicados anteriormente en la literatura, que demuestran una reducción de s-Klotho en la enfermedad crónica de riñones, en nuestro estudio, la disminución rápida anual de la función renal y no el nivel de eGFR se correlaciona con el crecimiento de s-Klotho. Una posible explicación podría ser una lesión tubular proximal más grave que podría llevar a la reducción de la excreción tubular de s-Klotho, sugerida por la correlación de s-Klotho con el nivel sérico de KIM-1

No clinical utility of common polymorphisms in IGF1, IRS1, GCKR, PPARG, GCK1 and KCTD1 genes previously associated with insulin resistance in overweight children from Romania and Moldova.

Background Previous genome-wide association studies (GWAS) identified IGF1, IRS1, GCKR, PPARG, GCK1 and KCTD1 as candidate genes for insulin resistance and type 2 diabetes (T2D). We investigated the associations of these previously reported common variants in these genes with insulin resistance in overweight children from Romania and Moldova. Methods Six single nucleotide polymorphisms (SNPs), IGF1 (rs35767), IRS1 (rs2943634), GCKR (rs780094), PPARG (rs1801282), GCK1 (rs1799884) and KCTD15 (rs29941), were genotyped in 100 overweight children along with clinical and metabolic parameters. Homeostatic model assessment of insulin resistance (HOMA-IR) above 3.4 (defining insulin resistance) was used as the outcome. Results Children differed in insulin resistance status despite having similar body mass index (BMI) standard deviation scores (SDS) (World Health Organization, [WHO] reference). The identified predictors for altered insulin metabolism were higher cholesterol levels, higher diastolic blood pressure and higher waist-to-hip-ratio (as a marker for increased abdominal fat). None of the SNPs showed significant association with increase in the risk for insulin resistance in children (p range=0.478-0.724; odds ratio [OR] range=1.924-4.842); however, the risk allele in GCKR (rs780094, p=0.06, OR=6.871) demonstrated near statistical significance. Conclusions The interrogated risk alleles did not show any significant association with insulin resistance in children in our cohort; however, the GCKR (rs780094) might be a viable candidate in larger cohorts. The lack of replication of the proposed association may point to differences in linkage disequilibrium or effect modifiers across studies.

Replaced right hepatic artery arising from inferior pancreaticoduodenal artery, in association with left multiple renal arteries: a case report using MDCT angiography.

The authors illustrate a case of a 61-year-old male who presented an extremely rare association of anatomical variations highlighted by multi-detector computed tomography (MDCT) angiography, with a replaced right hepatic artery (RRHA) arising from inferior pancreaticoduodenal artery (IPDA), in association with left multiple renal arteries (RAs). The celiac trunk (CT) arises from the abdominal aorta (AA), at the level of middle 1∕3 of L1 vertebral body. The superior mesenteric artery (SMA) origin was located at the anterior aspect of AA, at 2.5 mm below the origin of CT, at the level of L1∕L2 intervertebral discs. The SMA has at origin an endoluminal diameter of 11.3 mm. At 22.7 mm from its aortic origin, from the right aspect of the SMA trunk, arises IPDA. At 10.4 mm from its origin in IPDA, arises RRHA with a 78.5 mm artery length and the endoluminal diameter at origin of 2.9 mm. From the arising point, the RRHA is oriented ascending to the right, passing initially posterior to the hepatic portal vein and the head of the pancreas, then lateral to the head of the pancreas and posterior to the hepatic portal vein, after entering the hepatic parenchyma to bifurcate into the anterior and posterior branches. From left aspect of AA arise three RAs: one main, one additional (from AA), and an accessory renal (from left common iliac artery). Knowledge of this hepatic and renal anatomical variation is important for interventional radiologists, vascular experts, oncologists, vascular, hepatic and urologic surgeons.

Unilateral left four renal arteries: case report using MDCT angiography.

We report a very rare case of a 57-year-old male who presented four left renal arteries (RAs) [one main RA and three additional renal arteries (AdRAs)] highlighted incidentally on multidetector computed tomography (MDCT) angiography, which was used to investigate the vascular system of the lower limbs. The distance between the extreme points of RAs origin (upper and lower points of origin) from abdominal aorta (AA) was in the left part of 9.83 cm. The distance between the extreme points of penetration (upper and lower points of penetration) into the left renal parenchyma was 5.23 cm. At the level of origin, the main left RA has an endoluminal diameter of 0.63 cm, much larger in comparison to the other additional left RAs (0.43 cm, 0.33 cm and 0.28 cm, respectively). The length of the main left RA was 2.16 cm, significantly shorter in comparison with the other additional left RAs (2.21 cm, 4.26 cm and 4.73 cm, respectively). The second left RA was the main RA; the first left RA was AdRA (polar superior RA); the third left RA was AdRA (hilar RA); the fourth RA was AdRA (polar inferior RA). Knowledge of this anatomical variation should be considered in planning and performing renal vessel surgery, and kidney transplantation.

Hepato-spleno-mesenteric trunk, in association with an accessory left hepatic artery, and common trunk of right and left inferior phrenic arteries, independently arising from left gastric artery: case report using MDCT angiography.

The authors report the case of a 53-year-old male found to have an extremely rare case of a triple anatomical variation highlighted by multidetector computed tomography (MDCT) angiography, with the presence of a hepato-spleno-mesenteric trunk (HSMT) in association with an accessory left hepatic artery (ALHA) and a common trunk origin of right (RIPA) and left (LIPA) inferior phrenic arteries from left gastric artery (LGA) arising independently from the abdominal part of aorta (AA). The HSMT with an endoluminal diameter of 10.9 mm at its origin, and a length of 4 mm arose from the anterior wall of the AA at the level of 1∕2 upper part of the L1 vertebral body. From the distal portion of HSMT, give birth to the hepato-splenic trunk (HST) and to the superior mesenteric artery (SMA). HST, with a diameter at origin of 9.2 mm and 22.3 mm long, has an upward trajectory and done with the anterior face of AA an open angle to the top of 69°. From the distal part of the HST, arise common hepatic artery (CHA) and splenic artery (SA). The LGA, with an endoluminal diameter of 4.2 mm at origin, arose directly from the anterior wall of the AA at the level of the lower 1∕3 of T12 vertebral body, 8.2 mm above the origin of the HSMT. It ran upwards in front of the AA and after 59.5 mm gave rise to an ALHA. At 18.6 mm from its aortic origin, LGA gives birth to an inferior phrenic artery trunk (IPAT), which has at origin an endoluminal diameter of 2.6 mm and a length of 2.4 mm. The RIPA and LIPA have to origin a diameter of 2.3 mm and 1.7 mm, respectively. Knowledge of this anatomical variation is important for anatomists, interventional radiologists, vascular medicine experts, oncologists, vascular, and hepatic surgeons.

Common hepatic artery arising from the left gastric artery: a case report using MDCT angiography and a brief review of the literature.

We report a very rare case of a 67-year-old male with the presence of a common hepatic artery (CHA) arising from the left gastric artery (LGA) in association with a presence of a gastro-splenic trunk (GST), found incidentally on multidetector computed tomography (MDCT) angiography, used to investigate peripheral vascular disease. The GST arises from the anterior aspect of the abdominal aorta (AA), at the level of lower 1∕3 of L1 vertebral body. The GST has a slightly concave trajectory to the right, and ends dividing into splenic artery (SA) and LGA. In the initial part of its trajectory, the SA it is wedged at 180°, pointing to the left, to the splenic hilum. The LGA has two different portions: the first dilated, initially oriented towards the higher, and then aligns to the infero-lateral left and gives birth to the second portion; the narrow portion, oriented initially horizontally, and then lower to the right. Dilated portion of LGA is continued with CHA. The CHA trunk is cuddling in a horizontal plane, at 180°, and is then oriented towards the fissure of the ligamentum venosum for entering in the liver parenchyma. At 51.7 mm from the origin, the CHA gives rise to the left hepatic artery (LHA), and after another 58 mm to the right hepatic artery (RHA), and finally continues with the gastroduodenal artery (GDA). Knowledge of this anatomical variation should be considered in planning and performing vascular surgery in the supramesocolic floor of the abdominal cavity.

Rapid decline of kidney function in diabetic kidney disease is associated with high soluble Klotho levels.

BACKGROUND: Klotho is found in two forms: a transmembrane form and a soluble form (s-Klotho). In order to be excreted, s-Klotho, that is too large to be filtered, will probably reach the proximal convoluted tubule by a transcytosis process. The aim of our study was to show the relationship between the levels of s-Klotho and tubular injury in patients with diabetic kidney disease (DKD), using as tubular injury marker the kidney injury molecule-1 (KIM-1). METHODS: Our study included 63 DKD patients (stages 1-5, mean eGFR 65.15±32.45ml/min) with a mean age 58.13±12 years. In all patients we determined serum levels of: KIM-1 and s-Klotho using ELISA, urinary albumin/creatinine ratio (UACR) and reduction in the estimated glomerular filtration rate (eGFR) per year. RESULTS: We found a strong statistically significant correlation of s-Klotho with the rate of reduction of eGFR/year (r=0.714, p=0.0004) and with the tubular injury marker KIM-1 (r=0.758, p=0.005) and strong correlations of UACR with the rate of reduction of eGFR/year (r=0.53, p<0.01), KIM-1 (r=0.49, p<0.05) and s-Klotho (r=0.52, p<0.01). CONCLUSION: Despite previous published data, that shows a decrease of s-Klotho in chronic kidney disease, in our study the rapid annual decline of kidney function but not the level of eGFR was associated with increased s-Klotho. A possible explanation could be a more severe proximal tubule injury that could lead to a reduction of tubular excretion of s-Klotho as suggested by the correlation of s-Klotho levels with the serum levels of KIM-1.

An anomalous origin of the gastrosplenic trunk and common hepatic artery arising independently from the abdominal aorta: a case report using MDCT angiography.

The authors describe a case of a 61-year-old female patient, which presented on multidetector computed tomographic (MDCT) angiography a gastrosplenic trunk (GST) and common hepatic artery (CHA) arose independently from abdominal aorta (AA). The GST arose from the anterior wall of the AA, at the level of upper edge of the L1 vertebral body. The left gastric artery (LGA) arose from the superior wall of the GST. The splenic artery (SA) continuous the path of GST. The CHA arose from the anterior wall of the AA, at the level of upper one third of the L1 vertebral body, at 15.3 mm above the origin of superior mesenteric artery (SMA). The incidence and developmental and clinical significance of this vascular variation is discussed with a detailed review of the literature.

Deregulated profiles of urinary microRNAs may explain podocyte injury and proximal tubule dysfunction in normoalbuminuric patients with type 2 diabetes mellitus.

MicroRNAs (miRNAs) are short non-coding RNA species that are important post-transcriptional regulators of gene expression. The aim of the study was to establish a potential explanation of podocyte damage and proximal tubule (PT) dysfunction induced by deregulated miRNAs expression in the course of type 2 diabetes mellitus (DM). A total of 68 patients with type 2 DM and 11 healthy subjects were enrolled in a cross-sectional study and assessed concerning urinary albumin:creatinine ratio (UACR), urinary N-acetyl-ß-D-glucosamininidase (NAG), urinary kidney injury molecule-1, urinary nephrin, podocalyxin, synaptopodin, estimated glomerular filtration rate (eGFR), urinary miRNA21, miRNA124, and miRNA192. In univariable regression analysis, miRNA21, miRNA124, and miRNA192 correlated with urinary nephrin, synaptopodin, podocalyxin, NAG, KIM-1, UACR, and eGFR. Multivariable regression analysis yielded models in which miRNA192 correlated with synaptopodin, uNAG, and eGFR (R2=0.902; P<0.0001), miRNA124 correlated with synaptopodin, uNAG, UACR, and eGFR (R2=0.881; P<0.0001), whereas miRNA21 correlated with podocalyxin, uNAG, UACR, and eGFR (R2=0.882; P<0.0001). Urinary miRNA192 expression was downregulated, while urinary miRNA21 and miRNA124 expressions were upregulated. In patients with type 2 DM, there is an association between podocyte injury and PT dysfunction, and miRNA excretion, even in the normoalbuminuria stage. This observation documents a potential role of the urinary profiles of miRNA21, miRNA124, and miRNA192 in early DN. Despite their variability across the segments of the nephron, urinary miRNAs may be considered as a reliable tool for the identification of novel biomarkers in order to characterize the genetic pattern of podocyte damage and PT dysfunction in early DN of type 2 DM.

Ectopic kidney with malrotation and bilateral multiple arteries diagnosed using CT angiography.

Right renal ectopia with malrotation was seen on a CT angiography in a 64-year-old male patient. Bilateral triple renal arteries were also revealed: one main (superior) renal artery and two accessory arteries (middle and inferior), all originating in the abdominal aorta. The renal arteries are disposed symmetrically. The main arteries and the accessory ones are of equal caliber. Simple renal ectopia is a congenital malformation with an incidence of 1-2 cases in 1000 births; of these, only one of 10 cases is diagnosed. Like our case, many such cases are diagnosed by accident, during investigations of causes that have no connection with renal ectopia. Variations in kidney position and renal vascular variants are very important clinically, for both the complications they may generate and the technical difficulties of certain surgical interventions. CT angiography is a minimally invasive method that allows the identification of malformations or anatomic variations, providing accurate information on position, size and anatomic ratios, which are very useful in diagnosing and treating various affections.