Tubular Lesions Research Articles

Bone marrow-derived mesenchymal stem cells protect against cisplatin-induced acute kidney injury in rats by inhibiting cell apoptosis

Acute kidney injury (AKI) is a common syndrome with a high mortality and morbidity rate. Recent developments in stem cell research have shown great promise for the treatment of AKI. The aim of this study was to investigate the therapeutic potential and anti-apoptotic mechanisms of action of bone marrow-derived mesenchymal stem cells (BM-MSCs) in the treatment of AKI induced by cisplatin in vivo and in vitro. In vivo, adult male Sprague-Dawley rats (n=24) were administered BM-MSCs intravenously one day after cisplatin injection. The rats were sacrificed four days after the cisplatin injection and the effects of BM-MSCs on cisplatin-induced AKI, as well as the anti-apoptotic mechanisms involved were investigated. In vitro, NRK-52E cells, a rat renal proximal tubular cell line, were incubated in conditioned medium or complete medium in the presence or absence of cisplatin, followed by cell proliferation and apoptosis assays. The infusion of BM-MSCs preserved renal function, ameliorated renal tubular lesions, reduced apoptosis and accelerated tubular cell regeneration in the rats with cisplatin-induced AKI. The infusion of BM-MSCs also inhibited the activation of two mitogen-activated protein kinases, p38 and ERK, downregulated the expression of Bax and cleaved caspase-3, and upregulated the expression of Bcl-2. BM-MSC-conditioned medium improved NRK-52E cell viability and inhibited apoptosis. In conclusion, our results demonstrate that injecting rats with BM-MSCs protects renal function and structure in cisplatin-induced AKI by inhibiting cell apoptosis in vivo. BM-MSC-conditioned medium protects renal cells from apoptosis induced by cisplatin in vitro. Hence, the infusion of BM-MSCs should be considered as a possible therapeutic strategy for the treatment of AKI.

Urinary biomarkers in the early diagnosis of renal damage in diabetes mellitus patients

PURPOSE: The aim of this study was to determine the prevalence of tubular enzymes such as N-acetyl-β-D-glucosaminidase (NAG), alanine aminopeptidase (AAP) and gamma glutamyl transferase (γ-GT), α1-microglobulin, β2-microglobulin (β2-M) as well as microalbuminuria among patients with diabetes mellitus. MATERIAL AND METHODS: Biomarkers were evaluated in 285 type 1 diabetes mellitus patients and 30 healthy volunteers as a control group. Urinary levels of tubular enzymes such as NAG, AAP and γ-GT as well as microalbuminuria, α1-microglobulin and β2-M were determined by routine methods. Diabetes mellitus patients were divided into two groups - with normoalbuminuria (3-30 mg/L) and microalbuminuria (31-300 mg/L). RESULTS: Compared with healthy individuals, diabetes mellitus patients with normoalbuminuria excreted significantly higher levels of urinary NAG (p<0.05). In patients with microalbuminuria, the most significant changes of urinary NAG, AAP and g-GT, serum cystatin C and β2-M (p<0.001) were established. There was no significant difference between the patients and controls in respect to serum/urine creatinine. Urinary α1-microglobulin level was higher in the patients with poor glucose control (HbA1c >8.5%) and directly related to albuminuria. A significantly decrease of creatinine clearance in these patients was found out, too. CONCLUSION: Measuring the urinary NAG excretion, α1-microglobulin and cystatin C could be useful for the assessment of renal failure in diabetes mellitus patients. The activity of AAP and γ-GT is a less sensitive indicator of tubular lesions. The levels of β2-M and cystatin C which diagnostic accuracies are superior to those of serum creatinine represent early indicators of incipient diabetic nephropathy. Therefore, urinary biomarkers are useful in early detection of tubular and glomerular lesions in type 1 diabetes mellitus patients. Scripta Scientifica Medica 2013; 45(3): 58-64.

English

Cystic malformation of the seminal vesicle is rare congenital urogenital tract anomaly. It can be isolated anomaly. It can be associated with other urinary tract anomalies. Clinical presentation may be extremely variable. In symptomatic patients surgical intervention is required so radiological features and clinical aspects are very important for patient's management. CASE REPORT: A 32 yr male patient was admitted with complaints of dysuria, frequency of micturition and intermittent febrile episodes since last two months. A long course of antibiotics was given to him with clinical diagnosis of urinary tract infection. At the time of admission urine examination was normal. Per rectal examination revealed a firm mass located just superior to the prostate. Ultrasound of the abdomen and pelvis was performed which revealed absence of right kidney and hypertrophy of contralateral kidney which was also malrotated and improperly ascended. There was a cystic lesion at the anatomical site of seminal vesicle which is not seen separately, the prostate also appeared smaller in size. Transrectal ultrasound was performed for further characterization which revealed a large tubular cystic lesion entirely replacing the seminal vesicle. There was no solid component. The prostate was well visualized however it was smaller in size. Patient was further investigated with IVU, CT scan and MRI. Intravenous urography revealed absent right kidney and compensatory hypertrophy of left kidney. Left kidney was malrotated and incompletely ascended however it showed prompt and normal excretion. The left ureter and urinary bladder were normal. Plain and post intravenous contrast CT scan of the abdomen was performed. There was hypodense mass lesion of water attenuation in the pelvis at the bladder base more to the right side with non visualization of the seminal vesicles separately. There was no contrast enhancement. Plain MRI was performed using dedicated pelvic coil on 1.5 T GE units. Axial, coronal and sagittal T1W and T2 W sequences were performed. It showed a tortuous tubular structure of fluid signal intensity entirely replacing the seminal vesicles. It measured approximately 8x7x6 cms in size. There was no solid component. The prostate was small in size however appeared normal in morphology and signal characteristics. The rest of the pelvic structures were normal. So based on the imaging findings diagnosis of congenital cystic anomaly of the seminal vesicle was made. DISCUSSION: Congenital cysts of seminal vesicles can be subcategorized as isolated cysts, cysts associated with upper urinary tract anomalies and cysts associated with autosomal dominant polycystic kidney disease. Cysts of seminal vesicle usually become apparent during second to third decade of life, perhaps related to onset of sexual activity at this age(1). Cysts are mostly smaller than 5 cm in diameter and are often discovered incidentally, but they may present with a wide variety of

Is the urinary biomarkers assessment a non-invasive approach to tubular lesions of the solitary kidney?

Introduction: The solitary kidney (SK) is currently debated in the literature, as living kidney donation is extensively used and the diagnosis of congenital SK is frequent. Tubulointerstitial lesions associated with adaptive phenomena may occur early within the SK. Aims: Analysis of the significance of urinary biomarkers in the assessment of tubulointerstitial lesions of the SK. Methods: A cross-sectional study of 37 patients with SK included 18 patients—acquired SK (mean age 56.44 ± 12.20 years, interval from nephrectomy 10.94 ± 9.37 years), 19 patients—congenital SK (mean age 41.52 ± 10.54 years). Urinary NAG, urinary alpha-1-microglobulin, albuminuria, eGFR (CKD-EPI equation) were measured. Results: In acquired SK, NAG increased in 60.66%, urinary alpha 1-microglobulin in 16.66%, albuminuria in 55.55% of patients. Inverse correlation with eGFR presented NAG (R2 = 0.537, p = 0.022), urinary alpha 1-microglobulin (R2 = 0.702, p = 0.001), albuminuria (R2 = 0.655, p = 0.003). In congenital SK, NAG increased in 52.63%, urinary alpha 1-microglobulin in 5.26%, albuminuria in 47.36% of patients. In this group, urinary biomarkers correlated inversely with eGFR: NAG (R2 = 0.743, p < 0.001), urinary alpha 1-microglobulin (R2 = 0.701, p = 0.001), albuminuria (R2 = 0.821, p < 0.001). Significant correlations were found between the urinary biomarkers in both groups. Conclusions: Urinary biomarkers allow a non-invasive, sensitive, early assessment of the tubular lesions of the SK. Urinary biomarkers of PT injury parallel renal function decline, thus complementing the estimation of GFR. Monitoring of PT dysfunction is mandatory in patients with SK.

Ultrasonic Stimulation of the Cholinergic Anti-Inflammatory Pathway for Renal Protection

AKI encompasses a large spectrum of pathophysiological processes starting from the early reversible proximal tubular lesion to the definite loss of glomerular filtration and even death. Even discrete AKI ( i.e. , ≥0.3 mg/dl increase in serum creatinine in humans) has been reported to be associated

AB0018 Tubulointerstitial injury in lupus nephritis and gene expresion of KIM-1

BackgroundThe extent of tubular lesions and recruitment of inflammatory cells is belived to be and important predictor of renal function in immune- mediated glomerulonephritis (1) such as Lupus Nephritis (LN)....

Radiological findings in 31 patients with chondroblastoma in tubular and non-tubular bones

This study aimed to evaluate radiological findings in patients with chondroblastoma (CB) in tubular and non-tubular bones (NTBs). We retrospectively reviewed the medical records of patients with CB. Data collected included patients' gender and age, type, size and location of bone involved, and imaging findings regarding border, lobulation, calcification, trabeculation, cortical expansion and destruction, periosteal reaction, soft tissue component and fractures. Magnetic resonance imaging and/or multidetector computed tomography were used to determine the presence of any internal cystic space or secondary aneurysmal bone cyst that may have affected the radiological appearance of CB. All 31 lesions (18 tubular bones, 13 NTBs) exhibited geographic bone destruction and did not involve the adjacent joints. Univariate analysis showed that NTB lesions were found in older patients and were associated with thin trabeculation (p < 0.01) and well-defined margins (p < 0.05), whereas tubular bone lesions correlated with thick trabeculation and partially ill-defined margins. On multivariate analysis, age and type of bone involvement were significantly correlated. An increase in age by one year reduced the risk of having tubular bone involvement by about 27% when compared with NTBs (p = 0.011). Thin trabeculation was also significantly correlated with NTB lesions. Age was the most significant parameter, as increased age was found to reduce the risk of tubular bone involvement. Patients with NTB lesions were significantly older than those with tubular bone lesions. Based on imaging alone, thin trabeculation showed significant correlation with CB occurring in NTBs on both univariate and multivariate analyses.

Abstract 479: Expression of ApoE-sendai by Macrophages Causes Lipoprotein Glomerulopathy While Suppressing Atherosclerosis

Renal disease is usually associated with lipoprotein abnormalities. Lipoprotein glomerulopathy (LPG) is a unique disease characterized by intraglomerular lipoprotein thrombi, often in the absence of dyslipidemia. Macrophages are not involved in lipid accumulation in LPG. ApoESendai is an apoE variant known to cause LPG in heterozygous carriers. It carries the same charge as the apoE2 common variant, but is due to a proline-for-arginine substitution at position 145 in the apoE3 sequence. The effects of macrophage expression of apoESendai on LPG and atherosclerosis have not been studied.We have characterized renal and arterial responses in apoE-/- or apoE-/-/LDLR-/- (DKO) mice expressing apoESendai exclusively in macrophages. Bone marrow from apoE-/- mice was transduced with lentiviral constructs expressing either human apoE2 or apoESendai, and then transplanted into apoE-/- or DKO recipient mice.Compared to BMT controls, both apoESendai and apoE2 macrophages significantly decreased plasma cholesterol levels in apoE-/- recipients (22.6% and 19.4%, respectively). No changes in serum cholesterol levels were found in DKO recipients compared to controls. Macrophage expression of apoESendai and apoE2 was associated with plasma human apoE levels of 6.9±1.9 and 5.4±1.7 μg/ml, respectively, in apoE-/- recipients, and 18.9±2.8 and 18.4±3.8 μg/ml, respectively, in DKO recipients. All mice displayed extensive kidney tubular lesions, which correlated with the severity of dyslipidemia. While none of the apoE-/- recipients showed any additional kidney damage, DKO mice expressing apoESendai showed clear features of LPG, with lesions in the glomerular capillaries characterized by mesangial cell expansion. Macrophage apoE2 expression by apoE-/- BMT recipients reduced aortic lesion size by 22.7% compare to BMT controls (p&lt;0.01). Surprisingly, macrophage apoESendai expression further reduced aortic lesion size by 27.6% compared to apoE2 expression in apoE-/- mice (p&lt;0.01). A similar 26.1% reduction was seen in DKO recipients transplanted with apoESendai compared to apoE2 expressing macrophages.Our results show for the first time that macrophage expression of apoESendai protects against atherosclerosis while causing glomerular disease.

2113 INCREASED MATRIX METALLOPROTEINASE-9 IMMUNOEXPRESSION IN PROXIMAL TUBULAR EPITHELIUM AS AN EARLY SENSITIVE MARKER FOR SUBCLINICAL CALCINEURIN INHIBITOR NEPHROTOXICITY

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation, Renal Vascular Surgery1 Apr 20132113 INCREASED MATRIX METALLOPROTEINASE-9 IMMUNOEXPRESSION IN PROXIMAL TUBULAR EPITHELIUM AS AN EARLY SENSITIVE MARKER FOR SUBCLINICAL CALCINEURIN INHIBITOR NEPHROTOXICITY Kazuki Kitajima, Shiari Nozawa, Miki Yoshiike, Ryuto Nakazawa, Hideo Sasaki, Yuichi Sato, Junki Koike, Msayuki Takagi, and Tatsuya Chikaraishi Kazuki KitajimaKazuki Kitajima Kawasaki, Japan More articles by this author , Shiari NozawaShiari Nozawa Kawasaki, Japan More articles by this author , Miki YoshiikeMiki Yoshiike Kawasaki, Japan More articles by this author , Ryuto NakazawaRyuto Nakazawa Kawasaki, Japan More articles by this author , Hideo SasakiHideo Sasaki Kawasaki, Japan More articles by this author , Yuichi SatoYuichi Sato Kawasaki, Japan More articles by this author , Junki KoikeJunki Koike Kawasaki, Japan More articles by this author , Msayuki TakagiMsayuki Takagi Kawasaki, Japan More articles by this author , and Tatsuya ChikaraishiTatsuya Chikaraishi Kawasaki, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2022AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Calcineurin inhibitor nephrotoxicity (CNI-NT) has an adverse impact on long-term renal graft function. We have previously found that matrix metalloproteinase (MMP)-9 immunoexpression in the proximal tubular epithelium (PTE) was increased in renal allograft biopsies with acute clinical CNI-NT, which was reversibly decreased immediately after improvement in the clinical parameters. The objective of this study was to investigate the association of the MMP-9 expression in PTE with the pathological CNI-NT defined as histological characteristics. METHODS We examined 165 (85 protocol and 80 episode) biopsies from 80 recipients who received living-donor renal transplants under cyclosporine- or tacrolimus-based immunosuppression between 1998 and 2012. Biopsy specimens were immunohistochemically stained with anti-MMP-9 antibody, and the MMP-9 staining intensity in PTE was assessed by semi-quantitative scoring. Pathological CNI-NT was defined by the presence of cytoplasmic vacuolization of tubular epithelium (VAC) and/or arteriolar hyalinosis (AH). RESULTS Twenty-nine biopsies (11 with VAC and 23 with AH, including five with VAC+AH) showed pathological CNI-NT, and 24 of them (83%) were considered to be subclinical CNI-NT excluding the five biopsies that had been diagnosed as clinical ones. VAC was observed within 12 months (post-transplant period) in all the cases (11/11) and within two months in 64% (7/11), and significantly earlier than AH (mean±SD: 3.6±4.3 and 10.1±14.6 months, p<0.001). Interstitial fibrosis and tubular atrophy (IFTA) was colocalized in 48% (11/23) biopsies with AH, and 91% (10/11) of them were observed later than two months. The MMP-9 expression was positive in 100% (11/11) biopsies with VAC and 44% (8/18) of those with AH without VAC, while it was negative in 85% (28/33) without pathological lesions. CONCLUSIONS These findings suggest that subclinical CNI-NT occurs more frequently than expected, and the CNI-induced tubular lesion (VAC) develops earlier than the arteriolar one (AH). Prompt response to controlling CNI dosage by detecting the presence of VAC within the first two months after transplantation may help prevent irreversible pathological changes (e.g. IFTA) leading to chronic graft dysfunction. MMP-9 expression in PTE was found to be an extremely sensitive marker for VAC, and is not only useful for biopsy analysis but also promising as a non-invasive urinary marker. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e866 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kazuki Kitajima Kawasaki, Japan More articles by this author Shiari Nozawa Kawasaki, Japan More articles by this author Miki Yoshiike Kawasaki, Japan More articles by this author Ryuto Nakazawa Kawasaki, Japan More articles by this author Hideo Sasaki Kawasaki, Japan More articles by this author Yuichi Sato Kawasaki, Japan More articles by this author Junki Koike Kawasaki, Japan More articles by this author Msayuki Takagi Kawasaki, Japan More articles by this author Tatsuya Chikaraishi Kawasaki, Japan More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Pancreas and Islet Transplantation

Pancreas and Islet Transplantation

Liver and renal lesions in mercury-contaminated narwhals (Monodon monoceros) from North West Greenland

Narwhals (Monodon monoceros) from North West Greenland are known to bioaccumulate mercury (Hg) in tissues and internal organs. This is postulated to be a health concern and therefore studies were undertaken to conduct a screening study of Hg concentrations and histopathology of liver and renal tissues in a total of 12 specimens. The sample consisted of two sub-adults (one male, one female) and 10 adult (six males, four females) collected in Qaanaaq (Thule) 2010. In liver, Hg mean ± SD was 11.88 ± 10.47 μg/g ww (range: 0.39−31.8 μg/g ww) while the concentrations in kidneys were 1.85 ± 1.20 μg/g ww (range: 0.41−4.03 μg/g ww). There was no marked difference in Hg concentrations between males and females while sub-adults had significantly lower concentrations. The histological examinations of renal tissue showed glomerular capillary dilatation and basement membrane thickening, dilatation, and hyalinization of Bowman's space/capsule and tubular lesions with hyaline casts accompanied by interstitial fibrosis in the kidneys. In liver tissue, portal cell infiltrates and fibrosis, bile duct proliferation, lipid-filled Ito cells, and steatosis were found. There was no marked difference in histological prevalence between males and females and in Hg concentrations in individuals with or without lesions. Four of seven renal lesions and one liver lesion were found in the two sub-adult whales. Based upon these findings, as well as the nature of the lesions, evidence suggests that histopathological alterations were a result of age but that Hg might be an aggravating co-factor in development of renal lesions in particular.

Tubulointerstitial Nephropathies in HIV-Infected Patients over the Past 15 Years

The therapy and outcome of HIV infection have dramatically changed over the last 15 years, resulting in a change in renal complications. This study analyzed the characteristics of HIV-infected patients and biopsy-proven tubulointerstitial nephropathies to define disease patterns and therapeutic implications. A clinico-pathologic retrospective study of 59 consecutive renal biopsies showing predominant tubular and/or interstitial lesions in HIV-infected patients referred to the nephrology department between 1995 and 2011 was performed. HIV-associated nephropathy and vascular diseases were excluded from the study. Tubulointerstitial nephropathies accounted for 26.6% of 222 native renal biopsies performed in HIV-infected patients. Two pathologic groups were analyzed, tubulopathy and interstitial nephritis, which represented 49% and 51% of tubulointerstitial nephropathies, respectively. Most patients presented with AKI (76.3%) and high-grade proteinuria (57.7%). Drug-related nephrotoxicity was the leading cause (52.5%). Alternative etiologies included infections (15.2%), dysimmune disorders (8.5%), malignancies (3.4%), and chronic (10.2%) and acute (10.2%) tubulointerstitial nephropathies of undetermined origin. Tubulopathy was strongly associated with antiretroviral drug toxicity (75.9%) and mostly caused by tenofovir (55.2%), which was associated with proximal tubular dysfunction (87.5%), overt Fanconi's syndrome (37.5%), and nephrogenic diabetes insipidus (12.5%). Interstitial nephritis was associated with a broader spectrum of pathologic lesions and etiologies. In this series, tubulointerstitial nephropathies accounted for 26.6% of renal diseases in HIV-infected patients. Considering the therapeutic implications of diagnoses of drug toxicity, infection, and dysimmune syndromes, this study underscores the importance of monitoring renal parameters in HIV-infected patients and points to the relevance of kidney biopsy to allow an accurate diagnosis.

Abrogation of 5-flourouracil induced renal toxicity by bee propolis via targeting oxidative stress and inflammation in Wistar rats

Background5-fluorouracil (5-FU) is a strong anticancer agent however its clinical use is constrained because of its marked organ toxicity associated with increased oxidative stress and inflammation. The present study was designed to investigate the protective effects of bee propolis (BP), a naturally occurring bioflavonoid against 5-FU induced renal toxicity in Wistar rats using biochemical, histopathological changes and expression levels of inflammation. MethodologyWistar rats were subjected to concomitant pre and post-phylactic oral treatment of BP (80 and 160 mg/kg b.wt.) against nephrotoxicity induced by i.p. injection of 5-FU (75 mg/kg b.wt) and were sacrificed after 48 h. Nephrotoxicity was assessed by measuring the level of serum creatinine, BUN, LDH, KIM-1 and TNFα. The level of anti-oxidant defense enzymes of kidney tissue was also measured. ResultsTreatment with BP decreased the levels of serum toxicity markers significantly and additionally induced anti-oxidant defense enzyme levels as well as decreased expression of NFkB. Histopathological changes further confirmed the biochemical and immunohistochemical results showing that 5-FU caused significant structural damage to kidneys like tubular necrosis, renal lesions, glomerular congestion and dilated blood sinusoids were also observed. All these features of 5-FU induced toxicity were reversed by co-administration of BP. ConclusionTherefore, our study favors the view that BP may be a useful modulator in alleviating 5-FU induced nephrotoxicity.

Presumptive central nervous system cuterebriasis and concurrent protein‐losing nephropathy in a dog

To describe the clinical course and successful management of a dog suspected to have central nervous system (CNS) Cuterebra larval migration and concurrent protein-losing nephropathy (PLN). A 1-year-old castrated male mixed breed dog was diagnosed with presumptive CNS cuterebriasis based on history, progressively deteriorating mentation, seizures, and magnetic resonance images showing a tubular lesion consistent with a migrating Cuterebra tract. Additionally, serum biochemistry and urine analyses revealed the development of a severe PLN. Surgical removal of the Cuterebra was attempted unsuccessfully, and subsequently, the dog was treated with ivermectin, antihistamines, anticonvulsants, and a tapering dose of glucocorticoids. Over several weeks the dog's neurologic status improved and the PLN resolved completely. This case describes successful management of presumptive CNS cuterebriasis in a dog. It is also, to our knowledge, the first report of PLN associated with cuterebriasis in the veterinary literature.

Amide Hydrolysis of a Novel Chemical Series of Microsomal Prostaglandin E Synthase-1 Inhibitors Induces Kidney Toxicity in the Rat

A novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitor induced kidney injury at exposures representing less than 4 times the anticipated efficacious exposure in man during a 7-day toxicity study in rats. The findings consisted mainly of tubular lesions and the presence of crystalline material and increases in plasma urea and creatinine. In vitro and in vivo metabolic profiling generated a working hypothesis that a bis-sulfonamide metabolite (determined M1) formed by amide hydrolysis caused this toxicity. To test this hypothesis, rats were subjected to a 7-day study and were administered the suspected metabolite and two low-potency mPGES-1 inhibitor analogs, where amide hydrolysis was undetectable in rat hepatocyte experiments. The results suggested that compounds with a reduced propensity to undergo amide hydrolysis, thus having less ability to form M1, reduced the risk of inducing kidney toxicity. Rats treated with M1 alone showed no histopathologic change in the kidney, which was likely related to underexposure to M1. To circumvent rat kidney toxicity, we identified a potent mPGES-1 inhibitor with a low propensity for amide hydrolysis and superior rat pharmacokinetic properties. A subsequent 14-day rat toxicity study showed that this compound was associated with kidney toxicity at 42, but not 21, times the anticipated efficacious exposure in humans. In conclusion, by including metabolic profiling and exploratory rat toxicity studies, a new and active mPGES-1 inhibitor with improved margins to chemically induced kidney toxicity in rats has been identified.

PARP Inhibition Attenuates Histopathological Lesion in Ischemia/Reperfusion Renal Mouse Model after Cold Prolonged Ischemia

We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN) and other renal lesions related to prolonged cold ischemia/reperfusion (IR) in kidneys preserved at 4°C in University of Wisconsin (UW) solution. Material and Methods. We used 30 male Parp1+/+ wild-type and 15 male Parp10/0 knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ). We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp10/0 knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation.

Abnormal IgA1 O-Glycosylation in a Multi-ethnic population of IgA Nephropathy Patients in KwaZulu Natal, South Africa.

Abnormal IgA1 O-Glycosylation in a Multi-ethnic population of IgA Nephropathy Patients in KwaZulu Natal, South Africa.

The role of the toll-like receptor TLR4 in hepatitis B virus-associated glomerulonephritis

Toll-like receptor 4 (TLR4) plays an important role in innate immunity. The aim of our study was to detect the expression of TLR4 in HBV-associated glomerulonephritis (HBV-GN) and explore the pathogenesis of TLR4 in inhibition of HBV replication in kidney. Immunohistochemical methods were used to detect the distribution of immunoglobulin, HBsAg, HBcAg and TLR4. Because TLR4 was mainly distributed in renal tubules and interstitial spaces, we used human proximal tubular epithelial cells (HK-2) as target cells, which were cultured with HBV-DNA-positive serum. Cells were divided into four groups: A, a normal control group; B, an HBV-induced group; C, an HBV and 10μg/ml LPS (TLR4-stimulating factor) group; and D, an HBV and 5μg/ml CLI095 (TLR4 inhibitor) group. The morphology of HK-2 cells was observed by microscopy, and the expression of α-SMA was examined by immunofluorescence before and after culturing with HBV-DNA-positive serum. MTT was used to detect HK2 proliferation. The expression of TLR4 protein was detected by immunofluorescence and western-blotting assays, HBsAg and HBeAg levels in supernatants were measured by ELISA, and the expression of HBV-DNA was measured by semi-quantitative reverse transcription-PCR (RT-PCR). The immunohistochemical staining for TLR4 in the normal control group was negative. The expression of TLR4 in HBV-GN was significantly higher than in the HBV-antigen-positive and -negative primary glomerulonephritis (PGN) groups and was mainly distributed in renal tubules and the interstitial area, where the distribution of HBsAg had similar intensity. The expression of TLR4 was significantly associated with renal tubular and interstitial lesions. In an in vitro study with prolonged infection with HBV-DNA-positive serum, more irregularly shaped cells and fewer HK-2 were observed. The expression of α-SMA in the cytoplasm of HK-2 was significantly increased after HBV infection. Immunofluorescence results showed that almost no expression of TLR4 in HK2 cells cultured with normal serum (group A), while the expression of TLR4 was increased after HBV infection (group B). With increasing LPS concentration, the rate of the proliferation of HK2 cells, the levels of HBV-DNA in the supernatant, and the expression of HBsAg and HBeAg decreased. TLR4 was mainly expressed in HBV-GN in renal tubules and interstitial spaces and was significantly associated with renal tubular and interstitial lesions. The stimulation of TLR4 not only inhibited HBV replication but also inevitably induced immune injury to cells. Therefore, we speculate that TLR4 may be involved in an immune inflammatory reaction by inhibiting HBV replication in HK2 cells, which could have an antiviral effect during HBV infection in the kidney.

Clinical features of 8 cases of orbital sparganosis in southern China

ObjectiveTo describe clinicoradiologic characteristics of orbital sparganosis. DesignRetrospective case series. ParticipantsWe studied 8 patients diagnosed with orbital sparganosis at Zhongshan Ophthalmic Center between 1999 and 2011. MethodsA thorough review of clinical and imaging manifestations. ResultsThe primary clinical manifestations were redness and edema of the eyelids and conjunctivas (100%); proptosis (mild in 87.5% of cases and severe in 12.5%); subconjunctival yellow-white granulomatous lesions (75.0%); and migratory hyperemic masses of the eyelid or conjunctiva (50.0%). Of the patients, 6 had diffuse orbital or nodular masses on computed tomography imaging, 2 had the “tunnel sign” on magnetic resonance imaging, and 1 had subconjunctival tubular lesions on ultrasound biomicroscopy imaging. ConclusionsSubconjunctival yellow-white granulomatous lesions, migratory hyperemic masses, and the tunnel sign on magnetic resonance imaging are characteristic clues to preoperative diagnosis of orbital sparganosis.

Rapamycin-induced modulation of HIV gene transcription attenuates progression of HIVAN

HIV-associated nephropathy (HIVAN) is the manifestation of HIV gene expression by kidney cells in the presence of specific host factors. Recently, rapamycin (sirolimus) has been demonstrated to modulate the progression of HIVAN. We hypothesized that rapamycin would modulate the progression of HIVAN by attenuating HIV gene expression. To test our hypothesis, three weeks old Tg26 mice (n=6) were administered either vehicle or rapamycin (5mg/kg, every other day, intraperitoneal) for eight weeks. At the end of the experimental period, the kidneys were harvested. In in vitro studies, human podocytes were transduced with either HIV-1 (NL4-3) or empty vector (EV), followed by treatment with either vehicle or rapamycin. Total RNA and proteins were extracted from renal tissues/cellular lysates and HIV gene transcription/translation was measured by real time PCR and Western blotting studies. Renal histological slides were graded for glomerular sclerosis and tubular dilatation with microcyst formation. Rapamycin attenuated both glomerular and tubular lesions in Tg26 mice. Rapamycin decreased transcription of HIV genes both in renal tissues as well as in HIV-1 transduced podocytes. Our data strongly indicate that HIV-1 long terminal repeat-mediated transcriptional activity was targeted by rapamycin. Rapamycin enhanced podocyte NF-κB and CREB activities but then it decreased AP-1 binding activity. Since expression of HIV genes by kidney cells has been demonstrated to be the key factor in the development HIVAN, it appears that rapamycin-induced altered transcription of HIV genes might have partly contributed to its disease modulating effects.