mocetinostat and Nephritis

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Disease Models, Animal; Female; Glomerulonephritis; Male; Mercuric Chloride; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Mutation; Nephritis; Peroxidase; Rats; Vasculitis

We encountered an 86-year-old Japanese woman who presented with proteinuria (0.4 g/day) and hematuria (red blood cell sediment >100/high-power field), a decreased renal function (serum creatinine, 1.51 mg/dL), and elevated myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) levels (231 IU/mL) during treatment of rheumatoid arthritis with abatacept (a cytotoxic T-lymphocyte-associated antigen 4 agent) and adalimumab (a tumor necrosis factor-α agent). A kidney biopsy showed pauci-immune necrotizing glomerulonephritis, and ANCA-associated vasculitis was diagnosed. Treatment with tocilizumab (an interleukin 6 receptor antibody) monotherapy resulted in the improvement of renal findings and normalization of rheumatoid arthritis disease activity and serum ANCA levels. Tocilizumab can also suppress ANCA-associated vasculitis.

Topics: Abatacept; Adalimumab; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Arthritis, Rheumatoid; Female; Glomerulonephritis; Humans; Nephritis; Peroxidase

The value of myeloperoxidase (MPO) and proteinase 3 (PR3) antibody titres in the assessment of renal disease activity and flare prediction in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is not well known.. We performed a retrospective study including 113 AVV patients with renal biopsy-proven pauci-immune necrotizing glomerulonephritis from seven Spanish hospitals. The main inclusion criteria were assessment of MPO antibodies using multiplex flow immunoassay and PR3 antibody measurements using immunoassay chemiluminescence with an identical range of values for all participating centres.. Serum MPO antibodies 3 ± 1.2 months before relapse were higher in patients who relapsed [19.2 ± 12.2 versus 3.2 ± 5.1 antibody index (AI); P < 0.001]. The discrimination value of MPO antibodies 3 months before renal relapse had an area under the receiver operating characteristics curve (AUC) of 0.82 [95% confidence interval (CI) 0.73-0.92; P < 0.001]. ΔMPO antibodies (change in antibodies titration 6 months before relapse) were higher in patients who relapsed (8.3 ± 12 versus 0.9 ± 3.1 AI; P = 0.001). The discrimination value of ΔMPO had an AUC of 0.76 (95% CI 0.63-0.88; P < 0.001). The positive predictive value of renal relapse in PR3 patients is 100% and the negative predictive value of renal relapse in patients with PR3-positive titres is 57.1%. Serum PR3 antibodies were higher in patients who relapsed 2.8 ± 1.4 months before relapse (58.6 ± 24.6 versus 2.0 ± 0.6 AI; P < 0.001).. MPO level monitoring using multiplex flow immunoassay and PR3 measurements using immunoassay chemiluminescence are useful and sensitive tools for the prediction of renal relapse in the follow-up of AAV patients with renal disease and relevant surrogate markers of renal disease activity.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Kidney Diseases; Male; Myeloblastin; Nephritis; Peroxidase; Recurrence; Retrospective Studies

Myeloperoxidase anti-neutrophil cytoplasmic antibody-related nephritis (MPO-ANCA nephritis) is occasionally accompanied by lung abnormalities such as pulmonary fibrosis. However, the clinical features of pulmonary fibrosis in patients with MPO-ANCA nephritis have not been well documented. This study was performed to compare the prognosis of a usual interstitial pneumonia (UIP) pattern of lung fibrosis in patients with MPO-ANCA nephritis with the prognosis of idiopathic pulmonary fibrosis (IPF).. We retrospectively reviewed the medical records of 126 patients with MPO-ANCA nephritis and identified 31 with a UIP pattern of lung fibrosis on high-resolution or thin-slice computed tomography (CT). We compared the characteristics and prognosis of these patients with those of 32 patients with IPF. In 18 patients from both groups, we assessed and compared the decline in lung volume over time using three-dimensional (3D) CT images reconstructed from thin-section CT data.. The numbers of male and female patients were nearly equal among patients with MPO-ANCA nephritis exhibiting a UIP pattern; in contrast, significant male dominancy was observed among patients with IPF (p = 0.0021). Significantly fewer smokers were present among the patients with MPO-ANCA nephritis with a UIP pattern than among those with IPF (p = 0.0062). There was no significant difference in the median survival time between patients with MPO-ANCA nephritis with a UIP pattern (50.8 months) and IPF (55.8 months; p = 0.65). All patients with IPF in this cohort received antifibrotic therapy (pirfenidone or nintedanib). Almost half of the deaths that occurred in patients with MPO-ANCA nephritis with a UIP pattern were caused by non-respiratory-related events, whereas most deaths in patients with IPF were caused by respiratory failure such as acute exacerbation. In the 3D CT lung volume analyses, the rate of decline in lung volume was equivalent in both groups.. MPO-ANCA nephritis with a UIP pattern on CT may have an unfavorable prognosis equivalent to that of IPF with a UIP pattern treated with antifibrotic agents.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cause of Death; Female; Humans; Idiopathic Pulmonary Fibrosis; Imaging, Three-Dimensional; Lung; Male; Middle Aged; Nephritis; Peroxidase; Prognosis; Pulmonary Fibrosis; Respiratory Insufficiency; Retrospective Studies; Survival Rate; Tomography, X-Ray Computed

Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Blood Urea Nitrogen; Cisplatin; Creatinine; Immunosuppressive Agents; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Male; Malondialdehyde; Mice; Models, Animal; Nephritis; Nitric Oxide; Peroxidase; Random Allocation; Thalidomide; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The lung and kidney are two organs that are easily affected by hemorrhagic shock (HS). We investigated roles of biliary tract external drainage (BTED) in inflammation and edema of the lung and kidney in HS and its relationship with the heme oxygenase-1 (HO-1) pathway. Rat models of HS were induced by drawing blood from the femoral artery until a mean arterial pressure (MAP) of 40 ± 5 mmHg was achieved. A MAP of 40 ± 5 mmHg was maintained for 60 min. Thirty-six Sprague-Dawley rats were randomized to the following groups: sham group; HS group; HS + zinc protoporphyrin IX (ZnPP), a specific HO-1 inhibitor, group; HS + BTED group; HS + BTED + ZnPP group; and HS + BTED + bile infusion (BI) group. HO-1 levels, aquaporin-1 levels, and ratios of dry/wet in the lung and kidney increased markedly after BTED, but tumor necrosis factor-α and myeloperoxidase levels in the lung and kidney decreased significantly after BTED under HS conditions. Under the condition that HO-1 was inhibited by ZnPP, all these effects induced by BTED disappeared in the lung and kidney. These results demonstrated that inflammation and edema of the lung and kidney of HS rats are alleviated by BTED via the HO-1 pathway.

Topics: Animals; Aquaporin 1; Biliary Tract Surgical Procedures; Disease Models, Animal; Drainage; Enzyme Inhibitors; Heme Oxygenase (Decyclizing); Kidney; Lung; Male; Nephritis; Peroxidase; Pneumonia; Protoporphyrins; Pulmonary Edema; Rats, Sprague-Dawley; Shock, Hemorrhagic; Signal Transduction; Tumor Necrosis Factor-alpha; Up-Regulation

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is usually differentiated based on clinical phenotypes, but recent data indicate that myeloperoxidase (MPO)-AAV is genetically distinct from proteinase 3 (PR3)-AAV. We reviewed a population-based cohort of AAV, focusing on differences in clinical and laboratory characteristics and to compare renal outcome between MPO-ANCA and PR3-ANCA nephritis.. All new cases of AAV diagnosed between 1997 and 2009 in a geographically defined area in southern Sweden were retrieved using a validated search algorithm. Data were collected from time of diagnosis and end of followup. Renal and patient survival were analyzed according to ANCA serotype.. During the study period, 201 patients were diagnosed with AAV, 98 tested positive for PR3-ANCA, and 85 for MPO-ANCA. Patients with PR3-ANCA were younger, had significantly higher inflammatory activity, and had a larger number of organs involved at diagnosis, but nephritis was more prevalent among patients with MPO-associated (72/85; 85%) versus PR3-associated disease (67/98, 68%). When comparing only patients with ANCA-associated nephritis, those with MPO-ANCA were more likely to develop endstage renal disease (n = 27, 38%) than those with PR3-ANCA (n = 10, 15%), p = 0.003. The risk remained significantly elevated after adjusting for sex, age, and s-creatinine level at diagnosis (HR 2.64; 95% CI 1.25-5.58; p = 0.003). There were no significant differences in mortality rates between the 2 groups.. The outcome in this population-based cohort indicates that among AAV patients with nephritis, renal prognosis is better in the PR3-ANCA group, even after adjustment for sex, age, and renal function at diagnosis.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Humans; Kidney; Male; Middle Aged; Myeloblastin; Nephritis; Peroxidase; Prognosis

Nitroalkene derivatives of linoleic acid (nitrolinoleic acid; LNO2) and nitro-oleic acid (OA-NO2) are endogenous lipid products with potent anti-inflammatory properties. The present study was undertaken to evaluate the therapeutic potential of OA-NO2 in a mouse model of renal ischemia-reperfusion (I/R) injury. B6129SF2/J mice were subjected to bilateral renal ischemia for 30 min, followed by 24 h of reperfusion. Fifty minutes after ischemia, mice received intraperitoneal (ip) injections of OA-NO2 (500 microg/kg; I/R OA-NO2), vehicle for OA-NO2 (i.e., 0.8 ml/kg ethanol; I/R veh), or oleic acid (500 microg/kg; I/R OA) every 6 h during the 24-h recovery period. A sham-operated group was not subjected to ischemia and received 0.8 ml/kg ethanol ip every 6 h during the 24-h recovery period (sham veh). While plasma urea and creatinine were elevated (P<0.05) in I/R veh vs. sham veh mice, the severity was less (P<0.05) in I/R OA-NO2 animals. Indices of histological damage, polymorphonucleocyte infiltration, together with expression of intracellular adhesion molecule-1, interleukin-1beta, and tumor necrosis factor-alpha, p47(phox), and gp91(phox) were greater in I/R veh vs. sham veh mice, but were attenuated (P<0.05) in I/R OA-NO2 animals. Because indices of renal dysfunction were similar between I/R veh and I/R OA mice (P>0.05), but less (P<0.05) in I/R OA-NO2 animals compared with both groups, protection from bilateral renal ischemia is afforded by the nitrated but not free form of oleic acid. Together, delayed administration of nitrated fatty acid OA-NO2 attenuates renal I/R injury in the mouse likely via inhibition of the inflammatory response.

Topics: Acute Kidney Injury; Animals; Creatinine; Gene Expression; Injections, Intraperitoneal; Intercellular Adhesion Molecule-1; Interleukin-1beta; Kidney; Male; Membrane Glycoproteins; Mice; Mice, Inbred Strains; NADPH Oxidase 2; NADPH Oxidases; Nephritis; Nitrogen; Oleic Acids; Oxidative Stress; Peroxidase; Reperfusion Injury; Urea

We compared the histological changes before and after treatment in 14 cases of myeloperoxidase antineutrophil cytoplasmic autoantibodies (MPO-ANCA) related nephritis in whom we were able to perform two renal biopsies. The results show that the clinical findings and acute glomerular and tubulointerstitial injuries decreased, while chronic glomerular injuries increased. No changes were seen in minor glomerular abnormalities(MGAs) or chronic tubulointerstitial injuries between the first and second biopsies. In the vascular system, no treatment related aggravation of arteriosclerosis occurred and it was found that fibrinoid necrosis disappeared with treatment. Finally, in MPO-ANCA related nephritis, the care given between the first and second biopsies caused acute glomerular injuries to become chronic glomerular injuries, but no changes were detected in the MGA. We believe that the changes in acute tubulointerstitial injuries reflected an improvement in renal function, since the acute tubulointerstitial injuries obviously improved in response to PSL, contributing to the improved renal function. In other words, MPO ANCA-related nephritis is a condition that involves "acute glomerulonephritis+ acute tubulointerstitial nephritis + angiitis," and it is thought that the characteristics of each are independent. We believe that the renal function improved as the acute tubulointerstitial nephritis improved, while the acute glomerular injuries developed into chronic glomerular injuries.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Female; Humans; Kidney; Kidney Glomerulus; Male; Middle Aged; Nephritis; Peroxidase

Microscopic polyangiitis is a necrotizing angiitis involving capillaries, venules, and arterioles. The vascular beds of various organs may be involved, causing varying presentations. To our knowledge, this is the first case of anti-myeloperoxidase (anti-MPO) antibody small-vessel vasculitis causing prostatic vasculitis. A 79 year-old nonsmoker American man presented with symptoms of fevers, malaise, weight loss, and cough. Urine analysis revealed hematuria. Blood tests were remarkable for an elevated prostate-specific antigen (PSA) and a serum creatinine of 3.1 mg/dl (baseline, 1.2 mg/dl). Computed tomography (CT) scan of the thorax revealed a 4.7-cm mass in the left lower lobe of the lung. Metastatic prostate cancer was suspected. Therefore, prostatic biopsy was performed. The biopsy revealed fibrinoid degeneration with vasculitic changes involving the arterioles. When evaluated by nephrology, his serum creatinine was 9.9 mg/dl. A renal biopsy was performed, which revealed focal segmental necrotizing glomerulopathy with microscopic vasculitis. All the serologies were normal, with the exception of low C4, and positive perinuclear antineutrophil cytoplasmic antibodies (ANCA) associated with anti-MPO. The patient was started on intermittent hemodialysis, steroids, and oral cytoxan. Despite treatment, with improvement of the respiratory and constitutional symptoms, the patient remained dialysis-dependent. He later decided to discontinue dialysis and subsequently expired. Vasculitic involvement of the prostate is an uncommon manifestation of microscopic polyangiitis. This bedazzling entity is challenging to diagnose and thus makes it difficult to treat in a timely manner.

Topics: Aged; Antibodies, Anti-Idiotypic; Antibodies, Antineutrophil Cytoplasmic; Humans; Kidney; Male; Nephritis; Peroxidase; Prostate; Prostatitis; Vasculitis

The role of poly(ADP-ribose) (PAR) glycohydrolase (PARG) in the pathophysiology of renal ischemia/reperfusion (I/R) injury is not known. Poly(ADP-ribosyl)ation is rapidly stimulated in cells after DNA damage caused by the generation of reactive oxygen and nitrogen species during I/R. Continuous or excessive activation of poly(ADP-ribose) polymerase-1 produces extended chains of ADP-ribose on nuclear proteins and results in a substantial depletion of intracellular NAD(+) and subsequently, ATP, leading to cellular dysfunction and, ultimately, cell death. The key enzyme involved in polymer turnover is PARG, which possesses mainly exoglycosidase activity but can remove olig(ADP-ribose) fragments via endoglycosidic cleavage. Thus, the aim of this study was to investigate whether the absence of PARG(110) reduced the renal dysfunction, injury, and inflammation caused by I/R of the mouse kidney. Here, the renal dysfunction and injury caused by I/R (bilateral renal artery occlusion [30 min] followed by reperfusion [24 h]) in mice lacking PARG(110), the major nuclear isoform of PARG, was investigated. The following markers of renal dysfunction and injury were measured: Plasma urea, creatinine, aspartate aminotransferase, and histology. The following markers of inflammation were also measured: Myeloperoxidase activity, malondialdehyde levels, and plasma nitrite/nitrate. The degree of renal injury and dysfunction caused by I/R was significantly reduced in PARG(110)-deficient mice when compared with their wild-type littermates, and there were no differences in any of the biochemical parameters measured between sham-operated PARG(110)(-/-) mice and sham-operated wild-type littermates. Thus, it is proposed that endogenous PARG(110) plays a pivotal role in the pathophysiology of I/R injury of the kidney.

Topics: Animals; Aspartate Aminotransferases; Creatinine; Glycoside Hydrolases; Isoenzymes; Kidney; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Nephritis; Nitrates; Nitrites; Peroxidase; Reperfusion Injury; Urea

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Biomarkers; Female; Humans; IgA Vasculitis; Interleukin-10; Nephritis; Peroxidase; Vasculitis

A 17-year-old woman was admitted because of proteinuria, microhematuria and liver dysfunction with increased antinuclear antibody and anti-myeloperoxidase antibody (MPO-ANCA). Fourteen months' previously, urinalysis and liver function showed normal range. At that time she suffered from tachycardia and weight reduction, diagnosed as Graves' disease, she was given propylthiouracil for treatment of her Graves' disease. The histological finding of renal biopsy was compatible with minor glomerular abnormalities. Liver biopsy finding was compatible with autoimmune hepatitis. After we had administered prednisolone, liver function returned to normal range and urine protein became negative. Then we performed subtotal thyroidectomy, and she was not given propylthiouracil. MPO-ANCA decreased gradually.

Topics: Adolescent; Antithyroid Agents; Autoantibodies; Female; Graves Disease; Hepatitis, Autoimmune; Humans; Nephritis; Peroxidase; Propylthiouracil; Treatment Outcome

Inducible nitric oxide synthase (iNOS)-deficient mice were used to examine the role of iNOS in Escherichia coli-induced urinary tract infection (UTI). The toxicity of nitric oxide (NO)/peroxynitrite to bacteria and host was also investigated. The nitrite levels in urine of iNOS+/+ but not iNOS/ mice increased after infection. No differences in bacterial clearance or persistence were noted between the genotypes. In vitro, the uropathogenic E. coli 1177 was sensitive to 3-morpholinosydnonimine, whereas the avirulent E. coli HB101 was sensitive to both NO and 3-morpholinosydnonimine. E. coli HB101 was statistically (P < 0.05) more sensitive to peroxynitrite than E. coli 1177. Nitrotyrosine immunoreactivity was observed in infected bladders of both genotypes and in infected kidneys of iNOS+/+ mice. Myeloperoxidase, neuronal (n)NOS, and endothelial (e)NOS immunoreactivity was observed in inflammatory cells of both genotypes. Our results indicate that iNOS/ and iNOS+/+ mice are equally susceptible to E. coli-induced UTI and that the toxicity of NO to E. coli depends on bacterial virulence. Furthermore, myeloperoxidase and nNOS/eNOS may contribute to nitrotyrosine formation in the absence of iNOS.

Topics: Animals; Antibodies; Colony Count, Microbial; Escherichia coli; Escherichia coli Infections; Female; Genotype; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nephritis; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites; Peroxidase; Peroxynitrous Acid; Tyrosine; Urinary Tract Infections

Topics: Acute Disease; Adult; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Hemorrhage; Humans; Lung Diseases; Male; Nephritis; Peroxidase; Scleroderma, Systemic; Syndrome; Time Factors; Vasculitis

Within a 3-year period after the Great Earthquake of Kobe (Japan) resulted in more than 6,000 deaths and complete destruction of the central area of Kobe City, 14 patients (group 1 [G1]) with myeloperoxidase (MPO)-antineutrophil cytoplasmic autoantibody (ANCA)-related angitis and/or nephritis presented to Nishi-Kobe Medical Center in western Kobe City. On the other hand, only 15 patients with this disease were encountered between 1990 and 1997 at Kyoto University Hospital in Kyoto City, which is located 80 km from Kobe City and was only minimally affected by the earthquake. These 15 patients and 1 patient who presented to Nishi-Kobe Medical Center before the Great Earthquake were classified as group 2 (G2). Although the average MPO-ANCA titer in G1 was almost the same as that in G2, G1 showed a significantly greater average value for white blood cells than G2 (11,321 +/- 4,369 versus 8,116 +/- 2, 389/microL; P < 0.05). Concerning renal function, a significant elevation in creatinine (Cr) levels at diagnosis (7.4 +/- 3.8 versus 2.1 +/- 1.4 mg/dL; P < 0.01) and rapidly declining rates of reciprocal Cr levels were noted in G1 (0.325 +/- 0.304 versus 0.087 +/- 0.069 dL/mg. wk; P < 0.01). The number of patients who required emergency hemodialysis was significantly greater in G1 than G2 (nine versus three patients; P < 0.02); however, the incidence of renal death and mortality were not significantly different between the groups. The number of patients who reported upper respiratory tract inflammation as an initial symptom was also significantly greater in G1 than G2 (eight versus two patients; P < 0.01). Moreover, patients in G1 experienced a significantly greater rate of severe pulmonary involvement during the hospital course than G2 (pulmonary hemorrhage, five versus no patients; interstitial pneumonitis, four versus two patients, respectively; P < 0.01). The relatively uniform and distinctive clinical features of the disease after the Great Earthquake, in conjunction with a high morbidity, suggest a relationship between disease development and this urban type of earthquake. Severely provoking air pollution caused by massive destruction and reconstruction of the city may have caused high frequencies of upper respiratory tract inflammation as an initial symptom and severe pulmonary involvement.

Topics: Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Disasters; Female; Humans; Japan; Lung Diseases; Male; Middle Aged; Nephritis; Peroxidase; Vasculitis

Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of tissue injury in organs subjected to ischemia. The mechanism that triggers inflammation and organ injury after ischemia remains to be elucidated, although different causes have been postulated. We investigated the role of apoptosis in the induction of inflammation and organ damage after renal ischemia. Using a murine model, we demonstrate a relationship between apoptosis and subsequent inflammation. At the time of reperfusion, administration of the antiapoptotic agents IGF-1 and ZVAD-fmk (a caspase inactivator) prevented the early onset of not only renal apoptosis, but also inflammation and tissue injury. Conversely, when the antiapoptotic agents were administered after onset of apoptosis, these protective effects were completely abrogated. The presence of apoptosis was directly correlated with posttranslational processing of the endothelial monocyte-activating polypeptide II (EMAP-II), which may explain apoptosis-induced influx and sequestration of leukocytes in the reperfused kidney. These results strongly suggest that apoptosis is a crucial event that can initiate reperfusion-induced inflammation and subsequent tissue injury. The newly described pathophysiological insights provide important opportunities to effectively prevent clinical manifestations of reperfusion injury in the kidney, and potentially in other organs.

Topics: Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Blood Urea Nitrogen; Caspases; Chemotaxis, Leukocyte; Cysteine Proteinase Inhibitors; Cytokines; Depression, Chemical; Drug Administration Schedule; Epidermal Growth Factor; Humans; In Situ Nick-End Labeling; Insulin-Like Growth Factor I; Ischemia; Kidney; Male; Mice; Neoplasm Proteins; Nephritis; Peroxidase; Protein Processing, Post-Translational; Recombinant Proteins; Reperfusion Injury; RNA-Binding Proteins

A 12-year-old girl with a main complaint of sever pain on the both knees was admitted to our hospital in October, 1995. She gave a three year history of recurrent arthralgia and purpuric rashes, and persistent microhematuria and proteinuria. She developed vesicles and purpuric rashes on the hands and auricles, morning stiffness, fever, uveitis and pericarditis. Laboratory findings showed an elevated level of erythrocyte sedimentation rate and iron-deficiency anemia. Serum perinuclear pattern ANCA with antimyeloperioxidase specificity (MPO-ANCA) was positive. A renal biopsy specimen disclosed a focal and segmental necrotizing glomerulonephritis with crescents. Our case fulfills the both diagnostic criteria for polyarteritis nodosa and juvenile rheumatoid arthritis. This is a rare case of MPO-ANCA associated vasculitis in children.

Topics: Antibodies, Antineutrophil Cytoplasmic; Arthritis, Juvenile; Child; Female; Humans; Nephritis; Peroxidase

Tissue subjected to a period of ischemia undergoes morphological and functional damage that increases during the reperfusion phase. The aim of the present work was to assess the possible improvement induced by exogenous administration of nitric oxide (NO) on renal injury and inflammatory reaction in an experimental animal model of renal ischemia-reperfusion (I-R).. Ischemia was achieved by ligation of the left arteria and vein for 60 min, followed first by contralateral nephrectomy and then reestablishment of blood flow. Molsidomine, used as an NO donor, was administered by systemic injection 30 min before reperfusion. The effect of molsidomine was compared with the effect of hydralazine, a non-NO donor hypotensive agent.. Treatment with molsidomine improved the renal dysfunction (increase in plasma creatinine and urea levels) caused by I-R. Moreover, molsidomine blunted the enhanced production of proinflammatory cytokines (tumor necrosis factor [TNF]-alpha and interleukin [IL] 1alpha), the increase in tissular levels of superoxide anions and oxygen free radical scavengers, and the neutrophilic infiltration observed in the ischemic kidney. One hundred percent survival was achieved in the group of animals treated with the NO donor, whereas the groups of animals undergoing I-R that did not receive molsidomine showed a 40% mortality from the second day after reperfusion.. The present work demonstrated that systemic treatment with an NO donor before reperfusion improved renal function and diminished inflammatory responses in a kidney subjected to an I-R process.

Topics: Animals; Blood Pressure; Cytokines; Free Radical Scavengers; Ischemia; Kidney; Kidney Function Tests; Male; Nephritis; Nitric Oxide; Peroxidase; Rats; Rats, Wistar; Reactive Oxygen Species; Renal Circulation; Reperfusion Injury; Superoxides; Survival Analysis

The presence and the pathogenetic role of circulating IgA reacting with neutrophil cytoplasmic antigens (IgA-ANCA) in patients with Henoch-Schönlein purpura (HSP) is still debated. This study was aimed to investigate some characteristics of serum IgA and macromolecular IgA in HSP patients, focusing on IgA-ANCA.. Eighty-seven HSP patients with biopsy proved renal involvement (51 adults and 36 children) enrolled in a multicentre study of the Italian Group of Immunopathology were investigated.. Significantly high levels of IgA immune complexes were found in both adults (P < 0.05) and children (P < 0.01), while the binding of IgA to jacalin, was significantly low in children with HSP (P < 0.01) only. Two series of ELISA were done for IgA-ANCA, in two different laboratories. Increased binding to PMN crude extracts (P < 0.01) without any modification in IgA binding to proteinase 3 was found by either specific ELISA. Conversely, the binding of IgA to myeloperoxidase (MPO) was found to be significantly (P < 0.05) increased with positive values in 25% of patients by one assay only. Three of four sera with positive IgA-MPO ANCA exhibited binding in Western-blot studies with the MPO preparation used in ELISA to a 28-kDa species. D-galactose and N-acetyl-glucosamine decreased the binding of serum IgA to MPO more in HSP than in controls (P < 0.05).. The conflicting reports on IgA-ANCA may reflect some atypical characteristics of the reaction which can be detected only by some ELISAs. We suggest that not an antigen-antibody reaction but a lectinic interaction due to abnormal composition of IgA carbohydrate side chains may account for the IgA-ANCA reaction in patients with HSP nephritis.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Blotting, Western; Child; Enzyme-Linked Immunosorbent Assay; Humans; IgA Vasculitis; Immunoglobulin A; Nephritis; Peroxidase

To investigate a possible role of anti-neutrophil cytoplasmic antibodies directed against myeloperoxidase (MPO-ANCA) in glomerulonephritis, we prepared anti-rat MPO antiserum by immunization of rat MPO into a rabbit. Then we administered anti-rat MPO antiserum (group 1) or normal rabbit serum (NRS) (group 2) into rats before injection of nephrotoxic serum (NTS), which induced nephrotoxic serum nephritis (NTN). Other groups of rats received either anti-rat MPO anti-serum (group 3) or NRS (group 4) before injection of NRS but not NTS. Rats in group 1 and group 2 were sacrificed at either 3 hours, 15 hours, or 14 days after NTS injection. Rats in group 3 and group 4 were sacrificed at 15 hours after the last NRS injection. By light microscopy, in rats with NTN sacrificed at 3 hours, counts of polymorphonuclear leukocytes (PMN) per glomerulus were 21.6 +/- 3.5 in group 1 and 8.4 +/- 1.7 in group 2 (P < 0.01). At 15 hours, massive glomerular fibrin deposits were observed in group 1 rats (fibrin score, 131 +/- 8), but not in group 2 rats (fibrin score, 27 +/- 21; P < 0.01). By direct immunofluorescence microscopy, rat MPO was found along glomerular capillary walls more intensely in group 1 rats than in group 2 rats. No pathological alterations were found in group 3 and group 4 rats. Further, renal elution studies revealed that eluted rabbit IgG contained anti-rat MPO antibodies in group 1 rats but not in group 3 rats. These results suggest that the anti-MPO antibodies are directly involved in the more severe glomerular lesions in group 1 rats via interactions with MPO itself or activation of PMN, which release various kinds of mediators including MPO.

Topics: Animals; Antibodies; Female; Immune Sera; Kidney Glomerulus; Nephritis; Peroxidase; Proteinuria; Rabbits; Rats; Rats, Wistar; Tissue Distribution

Sera from 210 patients with APSGN, were tested for the presence of ANCA (IgG-isotype). Indirect immunofluorescence (IF) on ethanol fixed human PMNs was used, and for those positive sera, ELISA kits for PR3 (Proteinase 3) and MPO (Myeloperoxidase) was performed. ANCA were detected in 9% (18 out of 210 cases) in a predominantly diffuse cytoplasmic staining pattern in 14 cases (77%), and in a perinuclear pattern in the remaining 4 cases (22%). Anti-MPO was found in 4 cases (C-ANCA 3; P-ANCA 1) and anti-PR3 was always negative. The presence of ANCA was significantly associated with a more severe glomerular disease as assessed by the serum creatinine value and the crescents formation. Longitudinal studies performed in 11 cases have shown that raised levels of these autoantibodies may persist for at least six months, without relationship with disease activity. Further studies are required to dilucidate the specificity of these autoantibodies, and if its presence is either an epiphenomenon of the heterogeneous humoral immune response in streptococcal infection, or they play some pathogenic role in APSGN.

Topics: Adolescent; Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Child; Child, Preschool; Female; Humans; Immunoglobulin G; Infant; Kidney; Male; Middle Aged; Myeloblastin; Nephritis; Peroxidase; Serine Endopeptidases; Streptococcal Infections