BACKGROUND: Toll like receptor (TLR), an element of innate immunity, is upregulated by Ischemia/reperfusion (IR) injury and may be involved in adaptive immune response. Immunosuppressive agents may increase or attenuate IR injury and TLR expression. To explore the involvement of TLRs in hypoxic tubular injury and modification by mycophenolic acid (MPA) rapamycin (RAP), this study examined TLR expression in hypoxia-induced human renal proximal tubular epithelial cells (HK-2). METHODS: HK-2 cells were cultured in keratinocyte-SFM media supplemented with epidermal growth factor and bovine pituitary extract. The Induction of hypoxia was achieved using GasPak pouch system. TLR 2, 3, and 4 mRNA expression was analyzed by real time RT-PCR using SYBR green and TLR 4 protein expression was evaluated by Western blot analysis. MPA at concentration of 100 nM and 1uM and RAP at concentration of 20, 50, and 100 nM were added to culture medium. RESULTS: TLR4 but noTLR2 or TLR3 mRNA expressions increased in hypoxic HK-2 cells at 24 and 48 hrs. TLR4 protein expression also increased in hypoxic HK-2 cells at 24 and 48 hrs. MPA (100 nM and 1uM) and RAP (20, 50, and 100 nM) decreased hypoxia-induced TLR4 mRNA expression in HK-2 cells compared to normoxia at 24 hrs. However, TLR4 protein expression was decreased only by RAP at 20 and 50 nM. CONCLUSIONS: The results suggest that RAP may modify hypoxic renal tubular damage by decreasing TLR4-mediated inflammatory and immune reactions.
Adaptive Immunity ; Anoxia ; Blotting, Western ; Epidermal Growth Factor ; Epithelial Cells ; Humans ; Immunity, Innate ; Immunosuppressive Agents ; Mycophenolic Acid ; RNA, Messenger ; Sirolimus ; Toll-Like Receptors

Amyotrophic lateral sclerosis is a rare disease. It is a fatal neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons which leads to muscle weakness and muscle wasting. Respiratory failure limits survival to 2-5 years after disease onset. Several clinical manifestations including dysphagia can result in reductions in both the quality of life and life expectancy. Dysphagia occurs at onset in about one third of case, although generally it occurs in later stage of the disease. Evaluation of dysphagia includes video-fluoroscopic swallow study, radiological esophagogram, flexible endoscopic examination, ultrasound examination, conventional manometry and electromyography. We report a case of amyotrophic lateral sclerosis in a 54-year-old man presenting oropharyngeal dysphagia which was diagnosed by high resolution esophageal manometry presenting abnormality of the upper esophageal sphincter.
Amyotrophic Lateral Sclerosis ; Deglutition Disorders ; Electromyography ; Esophageal Sphincter, Upper ; Humans ; Life Expectancy ; Manometry ; Middle Aged ; Motor Neurons ; Muscle Weakness ; Muscles ; Neurodegenerative Diseases ; Paralysis ; Quality of Life ; Rare Diseases ; Respiratory Insufficiency

A case of 42-year-oldI kidney transplant patient who developed invasive carcinama of the cervix after immunoauppresawe therepy is reported and the literature related to this diease is revuewed. The iatmgenic immunosuppresaionn renal transplantation recipients has been associated with increased incidence of malignancy in these patients. In particular, immunosuppressed women are al greater risk of developing cervical intraepithelial neoplasia and buman papillomavirus type 16 or 18 infection. So, all such individuals are required to receive periodic gynecologic examination before renal transplantation and at regular intervals thereafter so that the development of CIN may be diagnosed at an early Stage and treated effestively.
Allografts* ; Cervical Intraepithelial Neoplasia ; Cervix Uteri ; Female ; Humans ; Incidence ; Kidney ; Kidney Transplantation

We report our experience of renal polyomavirus infection after renal allograft leading to graft dysfunction. A fourty seven-years-old male patient, has been on Tacrolimus based dual immunosuppression, showed graft dysfunction with rising serum creatinine at post-transplant day 140. His graft function had been good without any acute rejection episode. A tentative diagnosis of acute rejection was rendered and core needle biopsy was performed. Viral infection was initially suggested by the occurrence of markedly enlarged tubular epithelial cells containing large nuclei with smudgy chromatin pattern. Confirmatory diagnosis of human polyomavirus induced interstitial nephritis was obtained by electron microscopy, which showed viral particles in the nuclei of tubular epithelial cells. After Tacrolimus was converted to cyclosporine, renal function was stabilized. A review of the literature indicates that asymptomatic infection, ureteric stricture, and hemorrhagic cystitis are other possible manifestations of polyomavirus in the human urogenital tract. According to some prior reports, polyomavirus induced interstitial nephritis might be a cause of graft loss. But our patient has retained a stable graft function with a chnange of immunosuppression.
Allografts* ; Asymptomatic Infections ; Biopsy, Large-Core Needle ; Chromatin ; Constriction, Pathologic ; Creatinine ; Cyclosporine ; Cystitis ; Diagnosis ; Epithelial Cells ; Humans ; Immunosuppression ; Male ; Microscopy, Electron ; Nephritis* ; Nephritis, Interstitial ; Polyomavirus Infections ; Polyomavirus* ; Tacrolimus ; Transplants ; Ureter ; Virion

Transplant glomerulopathy (TG) is a special form of glomerular injury in renal allografts. It affects varying proportions of glomeruli, which may have an influence on the amount of proteinuria or graft survival. We reviewed 32 cases of TG to evaluate histologic changes and graft outcome. The severity of TG as well as acute and chronic changes of the glomerular, tubulointerstitial and vascular compartment were scored according to Banff classification. There were 17 cases of cg1, 3 cases of cg2 and 12 cases of cg3. There was no significant difference in age, duration of transplant at time of biopsy and duration of follow-up between groups. Serum creatinine level and the degree of proteinuria were higher in cg3 and statistically significant. However, there was no difference in the degree of glomerulosclerosis, interstitial inflammation, fibrosis, tubular atrophy or vascular wall thickening between groups. Graft failure was present in 13 cases, mostly due to chronic rejection including sepsis and CMV infection in one case each. Five-year graft survival was 84.1% and was not significantly different from cases without TG. In conclusion, the severity of TG indicates profuse proteinuria, but does not affect graft outcome, which indicates tubulointerstitial and vascular pathology as being a more important prognosticator.
Allografts ; Atrophy ; Biopsy ; Classification ; Creatinine ; Fibrosis ; Follow-Up Studies ; Graft Survival* ; Inflammation ; Pathology ; Proteinuria* ; Sepsis ; Transplants*

An association between drug treatment for viral infections and severe cutaneous adverse reactions has been noted. We investigated six patients diagnosed with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) after being prescribed acetaminophen for suspected viral illnesses. Multiplex analysis was performed to measure cytokine levels in sera before and after treatment. IL-2Rα levels significantly decreased during the convalescence phase. Although acetaminophen is relatively safe, the drug can trigger SJS/TEN in patients with suspected viral infections. T-cells and monocytes may be key components of the link between viral infection and acetaminophen-induced SJS/TEN.
Acetaminophen* ; Convalescence ; Humans ; Monocytes ; Stevens-Johnson Syndrome* ; T-Lymphocytes

Renal allografts frequently suffer from ischemia/reperfusion injury, which is a major cause of delayed graft function in renal transplantation(Tx). Cyclosporine(CsA) is known to aggravate ischemic injury, which may further heighten graft dysfunction. To know the histopathologic features of renal ischemic/reperfusion injury and cyclosporoine nephrotoxicity, we performed renal Tx between Lewis rats with cold ischemia and with/without CsA. Rats were sacrificed 3, 5, 7 days, 2, 3 and 4 weeks post-Tx. Control rats received sham operation. The kidney was processed for light microscopy and stained with H-E, PAS. Furthermore, to know the distribution of thioredoxin peroxidase(TPx), a recently cloned antioxidant in this model, the kidney tissue was stained with antibodies against three subtypes of TPx; NKEF-A /PAG(TPx A), NKEF-B/TPx(TPx B) and Mer 5. Renal isografts showed acute tubular necrosis from 3 days and recovery by 7 days, which was prolonged in CsA treated rats with signs of tubular and vascular toxicity. In sham operated rats, TPx A was distributed in all tubular segments, most prominently in distal tubules(DT). TPx B was stained in DT and collecting ducts(CD) exclusively. Mer 5 was present mainly in S3 segment. Glomerular or vascular expression was not found. In isografts TPx A expression was increased in both proximal(PT) and DT, markedly in the nonnecrotic S1 segment till 1 week postTx and returned to normal pattern by 2 weeks. TPx B and Mer 5 expression were increased till 5 days postTx with stronger staining in DT than in PT. CsA sustained the tubular expression of TPx till 4 weeks postTx. In summary, TPx expression was increased in renal tubules of rat renal isografts suffering cold ischemia, and more prolonged with CsA therapy. Marked increase of TPx A expression in S1 segment of ischemic kidneys may indicate resistance against oxidant injury, especially in S1 segment.
Allografts ; Animals ; Antibodies ; Clone Cells ; Cold Ischemia ; Cyclosporine* ; Delayed Graft Function ; Isografts* ; Kidney ; Kidney Transplantation ; Microscopy ; Necrosis ; Peroxiredoxins ; Pilot Projects* ; Rats* ; Reactive Oxygen Species ; Thioredoxins ; Transplants

Rapamycin, a macrocyclic lactone, is effective in reducing the incidence of acute rejection after renal transplantation. The inhibitory effects of rapamycin on lymphocyte proliferation and the molecular mechanisms that were involved have been described. However, its effects on glomerular mesangial cells have not been clearly understood, and here, we examined the effect of rapamycin on platelet-derived growth factor (PDGF) - induced extracellular matrix synthesis as well as cell proliferation in mesangial cells. Rat mesangial cells were isolated from the glomeruli of Sprague-Dawley rats and cultured with Dulbecco's modified Eagles medium containing 20% fetal bovine serum. Different concentrations of rapamycin were administered 1 hour before the addition of 10 ng/ml of PDGF into growth arrested and synchronized cells. Cell proliferation was assessed by [3H]thymidine incorporation, total collagen synthesis by [3H]proline incorporation, and fibronectin secretion into the medium by Western blot analysis. In the mesangial cells, PDGF increased cell proliferation by 4.6-fold, total collagen synthesis by 1.8-fold, and fibronectin secretion by 3.2-fold. Rapamycin above 10 nM significantly inhibited PDGF-induced proliferation and collagen synthesis, but the treatment of rapamycin up to 1micrometer did not show any significant effects on PDGF-induced fibronectin secretion. These inhibitory effects of rapamycin on PDGF-induced mesangial cell proliferation and collagen synthesis reflect the potential value of rapamycin in the prevention and treatment of glomerulosclerosis in patients with chronic allograft nephropathy.
Animals ; Cells, Cultured ; Collagen/*antagonists & inhibitors/biosynthesis ; Fibronectins/*biosynthesis ; Glomerular Mesangium/cytology/drug effects/*metabolism ; Immunosuppressive Agents/*pharmacology ; Male ; Platelet-Derived Growth Factor/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Research Support, Non-U.S. Gov't ; Sirolimus/*pharmacology

No abstract available.
Veins*

Diffuse glomerular basement membrane (GBM) lamellation, reminiscent of Alport's syndrome, has rarely, and exclusively, been reported in renal allografts from pediatric donors to adult recipients. We report on a similar lesion, identified in a 42-year-old male, who received a kidney from an unrelated 21-year-old living male donor. The disease of the recipient was unknown. Renal allograft biopsies were performed 3.5 and 4.8 years after the renal transplantation, due to massive proteinuria and serum creatinine elevation. The histological features of both biopsies were similar, but more advanced in the second biopsy. Glomerular mesangium was widened and had an IgA deposit in the first biopsy. In addition to the presence of mesangial electron dense deposits, the GBM showed diffuse lamellation and splintering on the subepithelial side, but no definite deposits. In the second biopsy, IgA deposits were extended to the peripheral capillary walls, but electron microscopic examination was not available. Two months after the second biopsy, the patient returned for hemodialysis.
Adult ; Basement Membrane/*pathology ; Case Report ; Glomerulonephritis, IGA/*etiology/*pathology ; Human ; Kidney Glomerulus/*pathology ; *Kidney Transplantation/*adverse effects ; Male