Fibrinoid Necrosis Of Arteries Research Articles

Isolated arterial mucoid intimal thickening lesion in early post-transplant kidney allograft biopsies.

Thrombotic microangiopathy (TMA) on kidney biopsy shows a variable combination of features: arterial mucoid intimal thickening, acellular closure of glomerular capillary loops, fragmented red blood cells, fibrin thrombi, and arterial fibrinoid necrosis. However, some early post-transplant kidney biopsies show only arterial mucoid intimal thickening. We aimed to elucidate the importance of this finding. We identified 19 biopsies showing isolated arterial mucoid intimal thickening and compared them with 22 bona fide TMA biopsies identified based on the pathological findings (excluding rejection) (2011-2020). Additionally, delayed graft function (DGF) (n=237), and no DGF (control, n=1314) groups were included for survival analysis. Seven of 19 cases with isolated arterial mucoid intimal thickening showed peripheral blood schistocytes but no other systemic features of TMA. Eight patients underwent adjustments in maintenance immunosuppression (mainly calcineurin inhibitors). None of the cases progressed to full-blown TMA on consecutive biopsies. The overall and death-censored graft survival rates in this group were comparable to the DGF group, but significantly better than the TMA group (P=.005 and .04, respectively). Isolated arterial mucoid intimal thickening in early post-transplant biopsies may be an early/mild form of TMA, probably requiring adjustment in immunosuppressive regimen. Careful exclusion of known causes of TMA, and donor-derived arterial injury are important.

Pathological features of classical polyarteritis nodosa: Analysis of 19 autopsy cases

Classical polyarteritis nodosa (cPN) is a rare autoimmune disease featuring systemic inflammation of middle- and small-sized arteries. Because most of autopsy cases underwent clinical treatment, arterial fibrinoid necrosis, which is the most specific finding of cPN, is often obscure. The aim of this study was to seek morphological characteristics of the middle-sized arteries in autopsy cases of cPN, and to identify immunohistochemical markers for the diagnosis of cPN. Nineteen patients who had undergone autopsy with a diagnosis of cPN were enrolled. Twenty-one autopsy cases without cPN were examined as control group. Arterial fibrinoid necrosis in medium-sized arteries was observed in 8/19 autopsy cases. Elastica van Gieson staining showed an increased number of elastic fiber layers (P<0.0001) and greater distances between elastic fiber layers (P<0.0001) in the renal middle-sized arteries of the cPN group. These findings probably reflected the post-inflammatory remodeling process after necrotizing vasculitis. On immunohistochemical examination, the cPN group showed high matrix metalloproteinase-1 and tumor necrosis factor-α expressions and decreased smoothelin expression in the vascular wall compared to the control group. When uncertain or atypical autopsy cases of cPN are examined, these findings can help to make the pathological diagnosis of cPN.

Histopathology and outcome of acute humoral rejection in renal allografts

Our purpose was to see if histopathologic features of acute antibody-mediated rejection (AMR) in renal allografts have prognostic value; and to compare two-year graft survival with and without additional therapy with plasmapheresis and intravenous immunoglobulin (IVIG). We reviewed renal allograft biopsies taken within the first 6 months after transplant from patients with C4d positive AMR, performed between January 2000 to December 2005 (n=57). We formed two groups: Group 1: biopsied between 2003 and 2005 (n=26), when C4d staining was routinely performed and option for plasmapheresis and IVIG was available; Group 2: biopsied between 2000 and 2002 (n=31), retrospectively found to be C4d positive. Patients whose biopsies showed cortical necrosis or arterial fibrinoid necrosis had early graft loss. Other histopathologic features did not statistically correlate with graft loss. Overall, additional plasmapheresis/IVIG treatment did not show convincing improvement in graft survival or function at 2 years post-transplant, but all six patients with thrombotic microangiopathy (TMA) who received plasmapheresis/IVIG had functioning grafts at two-year follow-up.

Contribution of cytochrome P450 metabolites of arachidonic acid to hypertension and end‐organ damage in spontaneously hypertensive rats treated with l‐NAME

1 The purpose of this study was to examine the effect of inhibition of the formation of cytochrome P450 metabolites of arachidonic acid with 1-aminobenzotriazole (ABT) on the development of hypertension and end-organ damage in spontaneously hypertensive rats (SHR) chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). 2 Administration of L-NAME in drinking water (80 mg l(-1)) to SHR for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223 +/- 4 mmHg) as compared to SHR controls drinking regular water (165 +/- 3 mmHg). The administration of ABT (50 mg kg(-1) i.p. alt diem) for 6 days significantly attenuated elevation of blood pressure in SHR-L-NAME (204 +/- 4 mmHg). 3 L-NAME-induced increase in urine volume and protein was significantly lower in ABT-treated animals. 4 The impaired vascular responsiveness to noradrenaline and isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly improved by ABT treatment. 5 Morphological studies of the kidneys and hearts showed that treatment with ABT minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, significant narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. 6 In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischaemia was significantly better in ABT-treated SHR-L-NAME. 7 These results suggest that in hypertensive individuals with endothelial dysfunction and chronic NO deficiency, inhibitors of 20-HETE synthesis may be able to attenuate development of high blood pressure and end-organ damage.

Signal transduction involving Ras-GTPase contributes to development of hypertension and end-organ damage in spontaneously hypertensive rats-treated with L-NAME

The purpose of this study was to examine the effect of inhibition of Ras-GTPase mediated signalling on the development of hypertension and end-organ damage in spontaneously hypertensive rats chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). Administration of L-NAME in drinking water (80 mg/L) for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223 ± 4 mmHg) as compared to that of SHR controls (165 ± 3 mmHg). The administration of Ras-GTPase inhibitor FPTIII (232 ng/min) to SHR-L-NAME during the last 6 days significantly attenuated high blood pressure (192 ± 4 mmHg). Morphological studies of the kidneys and hearts showed that treatment with FPTIII minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. L-NAME-induced increase in urine volume and protein was also significantly lower in FPTIII-treated animals. The impaired vascular responsiveness to isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly attenuated by FPTIII treatment. In isolated perfused hearts, recovery of left ventricular function from a 40 min of global ischemia was significantly better in FPTIII-treated SHR-L-NAME. Treatment with FPTIII also significantly reduced expression of cardiac sodium–hydrogen exchanger-1 (NHE-1) which was elevated in SHR-L-NAME. These data indicate that inhibition of Ras-GTPase-mediated signalling can attenuate end-organ damage during severe hypertension and endothelial dysfunction.

Parésie trochléaire transitoire comme signe neurologique inaugural d’une panartérite noueuse

Panarteritis nodosa (PAN) is a systemic vasculitis affecting small and medium-sized arteries. Neuro-ophthalmological complications of PAN are rare but numerous, and may affect the eye, the visual and the oculomotor pathways. Such complications occur mainly in patients previously diagnosed with PAN. A 51-year-old woman presented with an isolated right trochlear (IV) palsy, in the setting of headaches and fluctuating fever of unknown etiology. Erythrocyte sedimentation rate was 13 mm and full blood cell count was normal. Previous chest X-ray and blood studies were negative for an infection or inflammation. Orbital and cerebral CT scan was normal. Spontaneous recovery of diplopia ensued over four days. Two days later, paresthesia and sensory paresis of the dorsal portion of the left foot were present. Lumbar puncture revealed 14 leucocytes (76 percent lymphocytes) with elevated proteins, but blood studies and serologies were negative. A diagnosis of undetermined meningo-myelo-radiculoneuritis was made. Because of a possible tick bite six weeks previously the patient was empirically treated with 2 g intravenous ceftriaxone for 3 weeks. Fever rapidly dropped. Six weeks after the onset of diplopia, acute onset of blindness in her right eye, diffuse arthralgias and fever motivated a new hospitalization. There was a central retinal artery occlusion of the right eye. Blood studies now revealed signs of systemic inflammation (ESR 30 mm, CRP 12 mg/L, ANA 1/80, pANCA 1/40, leucocytosis 12.4 G/L, Hb 111 g/L, Ht 33 percent). Biopsy of the left sural nerve revealed arterial fibrinoid necrosis. A diagnosis of PAN was made. Transient diplopia can be the heralding symptom of a systemic vasculitis such as PAN, giant cell arteritis and Wegener granulomatosis. In this patient the presence of accompanying systemic symptoms raised a suspicion of systemic inflammation, but the absence of serologic and imaging abnormalities precluded a specific diagnosis initially. A few weeks later, the presence of a second ischemic event (retinal) and positive blood studies led to a further diagnostic procedure. Oculomotor and abducens palsies have rarely been reported in association with PAN. We report the first case of trochlear nerve paresis as the inaugural neurological sign of PAN. This case highlights the importance of considering inflammatory systemic disorders in patients with acute diplopia particularly when they are young, lack vascular risk factors or cause, and complain of associated systemic symptoms.

Cyclosporine toxicity in immunosuppressed streptozotocin-diabetic nonhuman primates

Streptozotocin (STZ) is widely applied in animal models of insulin-dependent diabetes mellitus. Adverse effects of STZ mainly concern liver and kidney. In nonhuman primates a single 100-150 mg/kg dose invariably induces diabetes with only rare adverse effects. We report one animal with renal failure necessitating sacrifice. Body weight (age) might be a confounding factor, i.e. older animals might be more vulnerable to STZ-related toxicity. We therefore recommended to administer STZ on a mg/m2 basis and not on a mg/kg basis. In our islet transplantation program nonhuman primates with STZ-induced diabetes received transplants under chronic immunosuppression including calcineurin inhibitors (cyclosporine, tacrolimus), drugs in the rapamycin class affecting growth factor-induced cell proliferation, and the sphingosine 1-phosphate receptor antagonist FTY720. Four animals developed renal failure and had to be sacrificed, most likely caused by cyclosporine. Kidney histology was typical for cyclosporine toxicity including thrombotic microangiopathy in glomeruli and fibrinoid necrosis of arteries, and for STZ toxicity including acute tubular necrosis and accumulations of erythroid precursors. This adverse effect was observed at a pharmacologically active cyclosporine exposure. Additionally, six diabetic animals without major adverse effects during cyclosporine or tacrolimus treatment are presented. We conclude that cyclosporine facilitates renal dysfunction in animals with STZ-induced diabetes, presumably related to an increased vulnerability to a toxic insult after STZ administration.

Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart.

We studied the role of aldosterone (aldo) in myocardial injury in a model of angiotensin (Ang) II-hypertension. Wistar rats were given 1% NaCl (salt) to drink and randomized into one of the following groups (n = 10; treatment, 21 d): 1) vehicle control (VEH); 2) Ang II infusion (25 ng/min, sc); 3) Ang II infusion plus the selective aldo blocker, eplerenone (epl, 100 mg/kg.d, orally); 4) Ang II infusion in adrenalectomized (ADX) rats; and 5) Ang II infusion in ADX rats with aldo treatment (20 micro g/kg.d, sc). ADX rats received also dexamethasone (12 micro g/kg.d, sc). Systolic blood pressure increased with time in all treatment groups except the VEH group (VEH, 136 +/- 6; Ang II/NaCl, 203 +/- 12; Ang II/NaCl/epl, 196 +/- 10; Ang II/NaCl/ADX, 181 +/- 7; Ang II/NaCl/ADX/aldo, 236 +/- 8 mm Hg). Despite similar levels of hypertension, epl and ADX attenuated the increase in heart weight/body weight induced by Ang II. Histological examination of the hearts evidenced myocardial and vascular injury in the Ang II/salt (7 of 10 hearts with damage, P < 0.05 vs. VEH) and Ang II/salt/ADX/aldo groups (10 of 10 hearts with damage, P < 0.05). Injury included arterial fibrinoid necrosis, perivascular inflammation (primarily macrophages), and focal infarctions. Vascular lesions were associated with expression of the inflammatory mediators cyclooxygenase 2 (COX-2) and osteopontin in the media of coronary arteries. Myocardial injury, COX-2, and osteopontin expression were markedly attenuated by epl treatment (1 of 10 hearts with damage, P < 0.05 vs. Ang II/salt) and adrenalectomy (2 of 10 hearts with damage, P < 0.05 vs. Ang II/salt). Our data indicate that aldo plays a major role in Ang II-induced vascular inflammation in the heart and implicate COX-2 and osteopontin as potential mediators of the damage.

Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification.

The incidence of acute humoral rejection (AHR) in renal allograft biopsies has been difficult to determine because widely accepted diagnostic criteria have not been established. C4d deposition in peritubular capillaries (PTC) of renal allografts has been proposed as a useful marker for AHR. This study was designed to test the relative value of C4d staining, histology, and serology in the diagnosis of AHR. Of 232 consecutive kidney transplants performed at a single institution from July 1995 to July 1999, all patients (n = 67) who developed acute rejection within the first 3 mo and had a renal biopsy with available frozen tissue at acute rejection onset, as well as posttransplant sera within 30 d of the biopsy, were included in this study. Hematoxylin and eosin and periodic acid-Schiff stained sections were scored for glomerular, vascular, and tubulointerstitial pathology. C4d staining of cryostat sections was done by a sensitive three-layer immunofluorescence method. Donor-specific antibodies (DSA) were detected in posttransplant recipient sera using antihuman-globulin-enhanced T cell and B cell cytotoxicity assays and/or flow cytometry. Widespread C4d staining in PTC was present in 30% (20 of 67) of all acute rejection biopsies. The initial histologic diagnoses of the C4d(+) acute rejection cases were as follows: AHR only, 30%; acute cellular rejection (ACR) and AHR, 45%; ACR (CCTT types 1 or 2) alone, 15%; and acute tubular injury (ATI), 10%. The distinguishing morphologic features in C4d(+) versus C4d(-) acute rejection cases included the following: neutrophils in PTC, 65% versus 9%; neutrophilic glomerulitis, 55% versus 4%; neutrophilic tubulitis, 55% versus 9%; severe ATI, 75% versus 9%; and fibrinoid necrosis in glomeruli, 20% versus 0%, or arteries, 25% versus 0%; all P < 0.01. Mononuclear cell tubulitis was more common in the C4d(-) group (70% versus 100%; P < 0.01). No significant difference between C4d(+) and C4d(-) acute rejection was noted for endarteritis, 25% versus 32%; interstitial inflammation (mean % cortex), 27.2 +/- 27% versus 38 +/- 21%; interstitial hemorrhage, 25% versus 15%; or infarcts, 5% versus 2%. DSA were present in 90% (18 of 20) of the C4d(+) cases compared with 2% (1 of 47) in the C4d(-) acute rejection cases (P < 0.001). The pathology of the C4d(+) but DSA(-) cases was not distinguishable from the C4d(+), DSA(+) cases. The C4d(+) DSA(-) cases may be due to non-HLA antibodies or subthreshold levels of DSA. The sensitivity of C4d staining is 95% in the diagnosis of AHR compared with the donor-specific antibody test (90%). Overall, eight grafts were lost to acute rejection in the first year, of which 75% (6 of 8) had AHR. The 1-yr graft failure rate was 27% (4 of 15) for those AHR cases with only capillary neutrophils versus 40% (2 of 5) for those who also had fibrinoid necrosis of arteries. In comparison, the 1-yr graft failure rates were 3% and 7%, respectively, in ACR 1 (Banff/CCTT type 1) and ACR 2 (Banff/CCTT type 2) C4d(-) groups. A substantial fraction (30%) of biopsy-confirmed acute rejection episodes have a component of AHR as judged by C4d staining; most (90%), but not all, have detectable DSA. AHR may be overlooked in the presence of ACR or ATI by histology or negative serology, arguing for routine C4d staining of renal allograft biopsies. Because AHR has a distinct therapy and prognosis, we propose that it should be classified separately from ACR, with further sub-classification into AHR 1 (neutrophilic capillary involvement) and AHR 2 (arterial fibrinoid necrosis).

Nephroprotection by long-term ACE inhibition with ramipril in spontaneously hypertensive stroke prone rats

The effect of life-long treatment with the ACE inhibitor ramipril on hypertension-induced histological changes in the kidney was tested in stroke-prone spontaneously hypertensive rats (SHR-SP). One-month-old pre-hypertensive SHR-SP were randomized into three groups of 45 animals each, and exposed via drinking water for their lifetime to a dose of: 1 mg.kg-1.d-1 ramipril (antihypertensive dose, HRA); 10 micrograms.kg-1.d-1 slight dose of ramipril (non-antihypertensive dose, LRA); or placebo. Histological and biochemical assessments were conducted after 15 months in ten rats each, when about 80% of the placebo group had died. Kidneys from placebo treated SHR-SP showed pronounced arterial wall hypertrophy and sclerosis, arterial fibrinoid necrosis, glomerulopathy and tubular interstitial injury that were, in concert with normalized blood pressure, completely prevented by HRA treatment. LRA treatment did not affect any blood pressure increase, and also attenuated the development of arterial wall hypertrophy, sclerosis and arterial fibrinoid necrosis, though to a minor extent only, but did not change glomerular and tubulointerstitial degeneration. These effects of ramipril were associated with a dose-dependent inhibition of plasma and renal tissue ACE activities as well as lower serum concentrations of creatinine, but there were no changes in serum potassium. Life-long HRA-induced ACE inhibition protects against hypertension-induced renal damages in SHR-SP. This is associated with a doubling of the lifespan in these animals.

Lead poisoning in six captive avian species.

Red-winged blackbirds (Agelaius phoeniceus), brown-headed cowbirds (Molothrus ater), common grackles (Quiscalus quiscula), mallards (Anas platyrhynchos), northern bobwhites (Colinus virginianus), and eastern screech-owls (Otus asio) were poisoned with a concentration of lead (Pb) acetate in the diet which was increased by 60% each week until half of the birds in each treatment group died; surviving birds and all control birds except screech-owis were then killed by euthanasia. An additional group of mallards was poisoned with Pb shot. The gizzards of mallards poisoned either way usually were stained with bile; some of these birds also had proventricular impaction. Most poisoned birds of the other species were emaciated but lacked other gross lesions caused by Pb poisoning. In birds other than mallards, Pb poisoning could not be diagnosed without histological or hematological examinations or analysis of tissues. Poisoned birds of all six species could be reliably separated from control birds by an increase in the protoporphyrin concentrations in the blood and by a decrease in the activity of delta-aminolevulinic acid dehydratase (ALAD) in red blood cells. Hepatic iron (Fe) concentrations varied so much among individual birds that even though median hepatic Fe concentrations increased in poisoned birds, hepatic Fe concentrations were not useful in identifying poisoned birds. Renal intranuclear inclusion bodies occurred in 83% of all birds dying from Pb poisoning. Nephrosis, myocardial necrosis, and arterial fibrinoid necrosis were occasionally present. Median hepatic Pb concentrations varied from 20 ppm (wet wt) in male red-winged blackbirds to 111 ppm in female northern bobwhites. Median renal Pb concentrations varied from 22 ppm in redwinged blackbirds to 190 ppm in female northern bobwhites. Hepatic and renal Pb concentrations varied substantially among birds within each species. Median hepatic and renal Pb concentrations of birds that died were not statistically different (p > 0.05) from those of birds that were killed. Lead shot and Pb acetate affected mallards similarly.

Bluetongue in free-ranging pronghorn antelope (Antilocapra americana) in Wyoming: 1976 and 1984.

At least 3,200 pronghorn (Antilocapra americana) died during a bluetongue (BT) epizootic in eastern Wyoming during late September and early October 1976. In August and September 1984, another BT epizootic occurred in northeastern Wyoming resulting in 300 known pronghorn deaths. In 17 pronghorn examined postmortem, hemorrhages and edema were the most common gross pathologic changes. Microscopic changes included hemorrhage, edema, arterial fibrinoid necrosis, lymphoid depletion in splenic and lymphatic follicles, and neuronal necrosis. Bluetongue virus serotype 17 was isolated from pronghorn in both epizootics. Mortalities ceased with the advent of cool weather in late September and October. Seventy-six of 94 pronghorn killed by hunters during the latter period of the 1976 epizootic, and 14 of 24 pronghorn killed 1 yr later had serologic evidence of exposure to BT virus. The reproductive rate in pronghorn was depressed to 47 fawns per 100 does in August 1977, but returned to 93 fawns per 100 does by 1978. Following the 1984 outbreak, the reproductive rate was similarly depressed, but the cause was confounded by other environmental and range conditions. Deer, mostly mule deer (Odocoileus hemionus), also died during both epizootics of what was presumed to be BT.

Effect of cyclosporin A upon second-set rejection of rat renal allografts.

With the use of a DA to LEW rat renal allograft model, the ability of cyclosporin A to influence a second-set rejection was investigated. Sensitization of LEW rats was accomplished by performing DA to LEW skin grafts 4 to 5 weeks before kidney allografting. Cyclosporin A was given to sensitized rats in doses of 10 or 25 mg/kg/day for 14 days from the time of renal transplantation. Neither dose was nearly as effective in prolonging kidney graft survival in sensitized rats as the 10 mg/kg/day dose was in prolonging kidney graft survival in unsensitized rats. In the 25 mg/kg/day dose, cyclosporin A was capable of suppressing antibody formation to the graft in sensitized recipients despite the presence of donor-specific antibodies at the time of renal transplantation. The 10 mg/kg/day dose of cyclosporin A did not, however, suppress antibody formation after renal transplantation in sensitized recipients. In both sensitized and unsensitized rats cyclosporin A was effective in ameliorating the histological findings of arterial fibrinoid necrosis and glomerular necrosis in the renal allografts. In neither sensitized nor unsensitized rats did cyclosporin A effect the mononuclear cell infiltration of the renal allograft.

Human renal allografts: Analysis of lesions in long-term survivors

Two hundred thrity-five renal allografts were transplanted into 211 drug-modified recipients at the Peter Bent Brigham Hospital during the period 1959 to 1970. Of these, 74 grafts have survived beyond 650 days. Biopsy specimens were taken from 18 kidney transplants in this long-surviving group. They were obtained for specific clinical indications at times beyond 650 days, and their study is the basis for this report. All 18 grafts showed intimal fibro-obliterative arterial lesions, and in seven these lesions were sufficiently severe to be a major cause of graft failure. In four of the latter the initimal lesion progressed rapidly following cessation of immunosuppressive therapy, and extensive deposits of IgM, β 1c, and fibrin were demonstrable by immunofluorescence. Fibrinoid necrosis of arteries with medial IgG deposits and neutrophilic infiltrates and acute cellular rejection were also present at such times. All grafts showed glomerular alterations of varying degrees consisting of devascularization, folding of glomerular basement membranes, focal hypercellularity, pedicel fusion, increased basement membrane thickening with subendothelial changes, altered mesangial substance, and focal-linear deposits of IgG, IgM, β 1c, or Fib, irrespective of the recipients' original disease. These changes were considered to be due to combinations of ischemia and rejection. Distinctive subepithelial deposits were noted in one kidney and may represent either recurrent or de novo glomerulonephritis. Spherular basement membrane inclusions suggestive of Herpesvirus capsid were noted in five grafts. Glomerular injury did not appear to be a primary cause of graft failure in any of these 18 recipients. Acute cellular rejection was seen as early as two days and as late as five years after transplantation. Immunofluorescent deposits of globulins were demonstrable in the tubular basement membranes in 12 grafts. At times these were associated with albumin deposits, possibly representing tubular dysfunction. IgA was identified in cytoplasmic granules of infiltrating eosinophils in grafts that showed chronic rejection. The lesions in arteries, glomeruli, and peritubular capillaries are probably due to rejection and may result from endothelial injury with subsequent thrombosis. Recipients of grafts with deteriorating function that show accumulations of microthrombi and lipophages in arteries on early biopsies, or that demonstrate intimal fibroproliferative lesions, glomerular basement membrane thickening, and deposits of fibrin in the vasculature in later biopsies should receive long-term antithrombotic therapy.