Porcine Salmonellosis

Renal vascular lesions associated with experimentally induced septicemic porcine salmonellosis consisted of fibrinoid necrosis of the vessel walls and fibrin thrombi within the lumina of interlobular arteries, afferent arterioles and glomerular capillary loops. Extrarenal vascular alterations were predominantly localized to the skin and the lungs. In these sites, too, mere fibrin thrombi were found in the capillaries, whereas mixed thrombi, consisting of fibrin, platelets, leucocytes and erythrocytes were present in larger vessels. The conclusion is drawn that the renal vascular injury is completely compatible to the generalized Shwartzman reaction, while the extrarenal vascular changes may only in part depend on this mechanism.     

Role of Leukocytes in Blood Coagulation and the Generalized Shwartzman Reaction

IN spite of intensive investigation, many of the factors which initiate blood coagulation and thrombosis remain obscure. The generalized Shwartzman phenomenon, which is due at least in part to intravascular coagulation, is classically obtained by two appropriately spaced, sub-lethal, intravenous doses of endotoxin given to rabbits and is characterized by disseminated thrombi in lungs, kidney and spleen; the characteristic lesion in the kidneys is renal cortical necrosis. Although the Shwartzman phenomenon can be prevented by anticoagulation^{1, 2}, its mechanism remains obscure. Leukocytes have been implicated as the mediators but only indirect evidence is available¹. Leukocytes also possess procoagulant and anticoagulant activity^3–5, the former, however, has always been considered too weak to be physiologically significant or able to cause intensive intravascular clotting with defibrination. We now have evidence that endotoxin given to rabbits may endow their leukocytes with considerable procoagulant activity in vitro, sufficient to produce intravascular clots in various organs when infused to untreated normal rabbits.     

Liquoid-Induced Arterial Lesions and the Generalized Shwartzman Reaction

Mural necrotic lesions were produced in renal afferent arteries in rabbits, pigs and blue foxes, by intravenous injections of Liquoid. These lesions were frequently accompanied by thrombosis in the affected arterial segments and invariably by “microthrombosis” in glomerular capillaries. Mural arterial lesions were always present in cases with evident macroscopic necrotic changes of the renal cortex. Necrotic arterial lesions, with thrombosis, were also observed in pulmonary arteries in all the animal species used in these experiments, i.e. rabbit, pig, blue fox, mouse and ferret.     

Apoptotic cell death of vascular endothelial cells and renal tubular cells in the generalized Shwartzman reaction

Abstract The participation of apoptotic cell death in the generalized Shwartzman reaction was examined. The generalized Shwartzman reaction was induced in mice by two consecutive injections of lipopolysaccharide. Vascular endothelial cells in various organs of those mice were stained positively by the in situ specific labeling of fragmented DNA. Renal tubules were also stained focally. It was suggested that apoptotic cell death might participate in the development of vascular endothelial cell damage and acute tubular necrosis in the generalized Shwartzman reaction. Simultaneous administration of anti-γ-interferon antibody in the preparative injection of lipopolysaccharide completely blocked apoptosis of vascular endothelial cells. Priming with recombinant γ-interferon instead of lipopolysaccharide could produce apoptosis of vascular endothelial cells. It was suggested that γ-interferon might play a critical role on sensitization of endothelial cells for apoptosis.     

Acute and chronic effects of chemically induced unilateral renal disease in rats.

Chemically induced unilateral renal disease was associated with a high incidence of proteinuria, diuresis, a morphological spectrum ranging from perinephritis to acute tubular or cortical necrosis, and unilateral or bilateral glomerular fibrinogen deposition during the first 2 wk after induction. Later, a decrease in proteinuria and return to normal urine output was not infrequently followed by recurrent proteinuria, hypergammaglobulinemia, morphological alterations, and deposition of IgG and beta1C on the glomerular basement membranes and mesangium of the contralateral kidney and the treated kidney. Intercapillary deposition of fibrinogen in association with IgG and beta1C was occasionally observed in one or both kidneys. The morphologic, immunohistologic, serologic, and chemical findings suggest that this model may be useful for further defining the course and prognosis of unilateral renal disease produced by vascular insufficiency.     

Hypertension and Nephrosclerosis: A Reappraisal and a New Theory of Renal Ischemia

An observation in human autopsy material showing a statistically close relationship between complicated atherosclerosis of the aorta, at or above the renal artery take-off, and nephrosclerosis of usual type (i.e. the “granular kidney” of essential hypertension) led to a study of platelet aggregates as a cause of renal lesions. The renal cortical surface is peculiarly sensitive to ischemic damage. When an embolic source, which sheds repeatedly, was placed in the thoracic aorta of rabbits, they became hypertensive. The hypertension persisted for six months, at which time the kidneys showed nephrosclerosis characterized by surface cortical lesions consisting of shrunken glomeruli and atrophical tubules, subtended by arterioles whose intimas showed fibrous thickening. It is suggested that the renal component of the hypertension so induced is transitory, serving as a trigger mechanism for sustained hypertension.     

Endotoxins in Animal Feedstuffs

Microbial heat stable endotoxins comprise part of most animal feedstuffs. These components have become the subject of considerable interest in later years because of the demonstration of acute toxicity, intravascular coagulation and generalized Shwartzman’s reaction in connection with intravenous injections of endotoxins (Nordstoga 1976). Endotoxins are normally present in the intestine of man and animals, but seem only to be absorbed under special conditions. Of particular interest is the “sudden infant death syndrome” which has been described for infants receiving cow milk (Di Luzio & Friedmann 1973). Absorption of endotoxins may also occur in adults e.g. in connection with γ-irradiation, immunosuppression, transplantations, severe traumatic lesions and burns (Nordstoga). It is supposed that endotoxins play an important role in the development of shock under these conditions (Nordstoga). Fine (1972) reported that exogenously administered endotoxins may break down the defence mechanisms and lead to continuous absorption of endotoxins from the intestine.     

Intrarenal blood flow distribution: effect of carotid occlusion.

In this study we have examined the influence of bilateral carotid occlusion on intrarenal blood flow distribution. Using labeled microspheres to determine intrarenal hemodynamics, bilateral carotid ligation in mannitol or saline expanded dogs resulted in an increase in outer cortical blood flow and a decrease in inner cortical flow. Total renal blood flow and glomerular filtration rate did not change significantly during carotid occlusion whereas the average mean arterial blood pressure rose from 130 to 166 mmHg. Inner cortical flow resistance increased substantially after carotid occlusion; outer cortical resistance was unchanged. These results suggest that bilateral carotid occlusion selectively activates inner cortical renal sympathetic fibers.     

Cystographie isotopique indirecte couplée à la scintigraphie rénale corticale et détection des reflux vésicorénaux chez les nourrissons et les enfants atteints de pyélonéphrite

Vesico-uretero-renal reflux (VRR) and urinary tract infection are closely linked. Without any treatment, reflux nephropathy, hypertension and renal dysfunction are very often encountered. That is why a precocious and reliable diagnosis of RVR should be made. Our retrospective study included 33 infants and children suffering from acute pyelonephritis (APN). They were explored by both 99mTc-MAG3 indirect isotopic cystography (IIC), 99mTc-DMSA cortical renal scintigraphy performed on the same day, and radiological retrograde cystography (RRC). A VRR was expected on the same side than the pyelonephritic kidney. Results from IIC versus RRC and versus renal cortical acute pyelonephritis lesions, which were proved by the “gold standard” DMSA scan, were obtained. IIC detected a same-sided VRR in 52% and CRR in 33% of our patients. Some of them had bilateral lesions. IIC detected an homolateral VRR in 59% instead of 38% with RRC (P < 0.05). IIC is a physiological noninvasive examination with a convenient sensitivity and dosimetry to search a VRR. Moreover, it gives in the same time interesting functional information on the kidneys and the urinary tract. Each of these characteristics can be favorably compared with RRC.     

Age-related non-neoplastic lesions in the heart and kidneys of Syrian hamsters of the APA strain

Spontaneous cardiac and renal lesions in APA hamsters were examined histopathologically. Myocardial degeneration, valvular thickening, coronary arterial degeneration and increase in heart weight were common in old hamsters. These changes, which suggest cardiac failure, seem to be related to cardiac thrombosis which predominantly affected the left atrium and was found in over 40% of each sex over 16 months of age. Neither glomerular amyloidosis nor arteriolar nephrosclerosis was detected. In general the histopathology of renal lesions in APA hamsters resembled that of the condition known as glomerulonephrosis in rats. Renal lesions occurred more frequently and more severely and developed more rapidly in females than in males. There was no apparent correlation between cardiac thrombosis and renal disease.     

Cytotoxic effect of ochratoxin A on the renal corpuscles of rat kidney: could ochratoxin A cause kidney failure?

To demonstrate that Ochratoxin A can cause kidney failure as the kidney is the primary target for OTA cytotoxicity. Ochratoxin A (OTA) is a mycotoxin found in our food. The cytotoxic effect of a low cumulative dose of OTA on the renal corpuscles of the kidney tissue has been investigated in this report. This study was based on two groups in which weaning albino rats were used: (1) control; (2) OTA-treated rats (289 μg/kg/day). After 28 days of treatment, a significant decrease in body weight, kidney weight and relative weight were detected in OTA treated rats. Serum creatinine and urea level were slightly elevated. These results revealed significant histological as well as ultrastructral lesions in the OTA treated group. The lesions included global congestion in the renal tissue and loss of demarcation between the cortex and medulla. The normal architecture of the renal corpuscles was destroyed and most of the corpuscles lost their ordinary look. The most apparent histopathological changes were urinary space disappearance and hypercellularity. In addition, congested, undifferentiated, atrophied, hypertrophied, fragmented, sclerotic, degenerated, and obliterated renal corpuscles were distinct. The ultrastructural lesions observed in the renal corpuscles in OTA on treated rats included; proliferation and swelling of the endothelial cells with occasional loss of fenestrae; narrowing of the capillary lumen; damaged podocytes with deteriorated secondary foot processes, hypertrophied and proliferated mesangial cells with expanded mesangial matrix. The endothelium was clearly defected and vacuolated, and lost its fenestrations in many glomerular capillaries. In addition, the glomerular basement membrane (GBM) became visibly thickened and tortuous. Necrotic glomerular cells were frequently observed. Pre-apoptotic cells were also seen. It was concluded that the exposure to relatively low OTA concentrations induced significant lesions to the renal corpuscles. Moreover, it activated oxidative damage and necrosis which can cause extensive damage to the kidney and ultimately kidney failure.     

Evaluation of the effect of autologous mesenchymal stem cell injection in a large-animal model of bilateral kidney ischaemia reperfusion injury

Objectives: Adult mesenchymal stem cells (MSC) have been proven to be of benefit to the kidney in different experimental models of renal injuries. All studies have been performed in valuable rodent models, but the relevance of these results to large mammals and ultimately, to humans remains unknown. Therefore, the aim of this study was to investigate the effect of MSC transplantation in an alternative ovine large-animal model of bilateral kidney ischaemia reperfusion injury.
Material and methods: Sheep were divided into three groups: one sham-operated group and two groups submitted to renal bilateral ischaemia for 60 min. Animals with ischaemia reperfusion injury were treated with injection of autologous MSCs or with vehicle medium.
Results: The model sheep presented with renal histological manefestations that closely resembled lesions seen in patients. Transplanted MSCs were found in glomeruli but not in tubules and did not express glomerular cell markers (podocin, von Willebrand factor), but functional evaluation showed no beneficial effect of MSC infusion. Morphological and molecular analyses corroborated the functional results. MSCs did not repair kidney parenchyma and failed to modulate cell death and proliferation or cytokine release (tumour necrosis factor-alpha, vascular endothelial growth factor alpha (VEGF-α), Bcl-2, caspase).
Conclusion: In this unique autologous large-animal model, MSCs did not exhibit reparative or paracrine protective properties.     

Expression of the major AgB histocompatibility complex antigens on different structural components of rat kidney and heart

We have analyzed the expression of the major AgB locus antigens on the parenchymal cell components of rat kidney and heart using (a) heterologous antisera raised against isolated molecules and (b) conventional alloantisera, directed to the serologically detectable AgB and Ia allodeterminants. A modified Staphylococcus aureus Cowan I rosette assay, enabling the characterization of the rosette-forming cell type from stained cytocentrifuged cell smears, was used. The AgB and Ia antigens were detected by both types of antisera on the “passenger” cells of either organ: the anti-Ia reacted especially strongly with a fraction of “passenger” lymphocytes, and anti-AgB also with the “passenger” erythrocytes. All kidney parenchymal components were nearly devoid of both AgB and Ia antigens: only a weak reaction was observed with the vascular endothelial, tubular, or glomerular cells after treatment of either type of antiserum. The heart endothelial cells expressed the AgB and probably some Ia: an intermediary intensive reaction was observed after treatment with heterologous or allospecific anti-AgB, and a weak reaction with anti-Ia. The heart myocardial muscle cells, on the other hand, were nearly devoid of both antigens: no reactivity with heterologous anti-Ia and only a marginal reactivity with heterologous or allospecific anti-AgB was observed.     

Prolonged Oliguria with Survival in Acute Bilateral Cortical Necrosis

Survival is uncommon in cases of acute bilateral cortical necrosis. Three cases admitted to the renal unit at Newcastle have regained useful renal function after oliguric phases of 38, 46, and 120 days.Prolonged periods of intermittent dialysis are justified in patients in whom a firm diagnosis of acute cortical necrosis is made.     

Importance of alcohol and drug abuse in psychiatric emergencies.

Three cases of acute bilateral renal cortical necrosis, each with a different clinical course, are discussed. One patient spontaneously recovered renal function after prolonged oliguria. This case should be added to the small number of similar case reports in the literature. The second patient recovered adequate renal function temporarily, but eventually required chronic hemodialysis and renal transplantation. There was pathological evidence of progression from focal to massive cortical necrosis. The third patient never regained renal function, but is well after dialysis and transplantation.The influence of modern theories of pathogenesis of the disease, and increased availability of dialysis, are discussed in relation to the initial prognostic assessment of the patient with cortical necrosis.     

Clues potentially distinguishing lytic lesions of multiple myeloma from those of metastatic carcinoma

This study was conducted to determine whether individual bony lesions are specific for recognizing multiple myeloma and thereby distinguish it from metastatic cancer and leukemia. The lytic skeletal lesions of multiple myeloma are characterized by sharply defined, spheroid lesions. They have smooth borders and effaced/erased trabeculae. Unique spheroid myeloma lesions appear to be responsible for the “punched out” appearance of affected bone. The total absence of remodeling in myeloma forms a contrast to irregular preservation of trabeculae and buttressing, isolated “fronts of” cortical bone “resorption” coalescing to confluence, and the “golf-ball surface” phenomenon observed in metastatic cancer. The uniform effacement of both cortical and trabecular bone in multiple myeloma also contrasts with some cortical preservation in metastatic cancer. Leukemic lesions are more numerous than those of myeloma, but they lack the latter's “space-occupied” appearance. The relatively small holes and “fronts of resorption” of leukemia are quite different from the “space-occupied” lesions of multiple myeloma. Uniform size is a characteristic traditionally attributed to the bone lesions of multiple myeloma. The occurrence of isolated examples of uniform size lesions in metastatic cancer and of variable size lesions in some individuals with multiple myeloma precludes unequivocal use of size in differential diagnosis. Fortunately, the newly recognized macroscopic characteristics appear to separate multiple myeloma from metastatic cancer, and also distinguish myeloma from leukemia. Am J Phys Anthropol 105:241–250, 1998. © 1998 Wiley-Liss, Inc.     

Cutting edge: IL-15 costimulates the generalized Shwartzman reaction and innate immune IFN-gamma production in vivo

Sequential administration of LPS to SCID mice results in the generalized Shwartzman reaction, manifesting as rapid mortality via cytokine-induced shock. Here we demonstrate that in vivo neutralization of IL-15 before LPS priming significantly reduced lethality in this reaction (p = 0.0172). We hypothesize that LPS priming induces IL-12 and IL-15 that costimulate NK cell-derived IFN-gamma. Such IFN-gamma may then in turn sensitize macrophages to elicit the Shwartzman reaction following a subsequent LPS challenge. Supporting this, IL-12 and IL-15 synergized to induce murine NK cell IFN-gamma production in vitro. LPS stimulation of SCID mouse splenocytes resulted in measurable IFN-gamma production, which was reduced when IL-15 was neutralized or IL-2/15Rbeta was blocked. Pretreatment with either anti-IL-2/15Rbeta or anti-IL-15 Abs reduced serum IFN-gamma protein following LPS administration to SCID mice. Collectively, these data provide the first in vivo evidence that IL-15 participates in LPS-induced innate immune IFN-gamma production and significantly contributes to the lethal Shwartzman reaction.     

Nephrotoxic Lesions from 5-Aminosalicylic Acid

5-Aminosalicylic acid given to rats as a single intravenous injection led to necrosis of the proximal convoluted tubules and of the renal papilla. These two lesions developed at the same time and the cortical lesions did not appear to be a consequence of the renal papillary necrosis. Since the compound possesses the molecular structure both of a phenacetin derivative and of a salicylate these observations may be relevant to the problem of renal damage incident to abuse of analgesic compounds and suggest the possibility that in this syndrome cortical lesions may develop independently of renal papillary necrosis.     

Renal papillary necrosis in the tiger

Two examples of renal papillary necrosis in the tiger are described. The necrosis was characterised by large zones of liquefaction with minimal inflammation and was associated with pronouced scarring in the cortex. Both animals had been vomiting terminally and were severely dehydrated. It is suggested that papillary necrosis was precipitated by the reduced renal perfusion associated with dehydration in kidneys in which the medullary blood supply was already compromised by chronic cortical scarring. Comparisons are made between the lesions described in these tigers and those reported in the domestic cat, man and other domestic animals.