Lesions of the renal papilla induced by paracetamol

The acute nephrotoxic effects of paracetamol in the uninephrectomized homozygous Gunn rat are different from those of aspirin. Both compounds induce renal papillary necrosis but paracetamol produces accumulation of non-cellular material in the interstitial space, less damage to interstitial cells, more damage to tubular epithelium, and more severe necrosis of proximal convoluted tubules. In both cortex and papilla only a small fraction of the cells at risk are affected. It is concluded that the findings are consistent with a synergistic nephrotoxic effect between the two compounds, but that the lesions are not sufficiently severe for the natural history of analgesic nephropathy to be wholly explicable by such synergism.     

Experimental pyelonephritis and papillary necrosis in the Gunn rat

Homozygous and heterozygous female Gunn rats show increased susceptibility to experimental urinary infection. The strain develops pyelonephritis after intravesical inoculation of Proteus mirabilis in numbers which fail to induce the lesion in albino rats, and severe pyelonephritis is frequently complicated by papillary necrosis. The basis for this enhanced susceptibility has not been defined, but the occurrence of the phenomenon in both homozygous and heterozygous rats indicates that it is not caused primarily by high plasma levels of unconjugated bilirubin or by the deposition of bilirubin in the tip of the renal papilla. The increased susceptibility of the homozygous Gunn rat to ascending urinary tract infection provides supporting evidence for the suggestion that infection may complicate the natural history of experimental analgesic nephropathy in this strain and is relevant to the clinical association of analgesic nephropathy and urinary infection.     

Histochemistry and ultrastructure of the interstitium of the renal papilla in rats with hereditary diabetes insipidus (brattleboro strain)

The Brattleboro strain of Long-Evans hooded rats has hereditary hypothalamic diabetes insipidus due to the inability to produce antidiuretic hormone. Animals homozygous for this autosomal recessive trait have extreme polyuria and polydipsia, whereas heterozygotes are less severely affected. Light and electron microscopy were used to study the interstitial tissue of the renal papilla of Brattleboro rats and normal Long-Evans rats. Staining with alcian blue or colloidal iron revealed that homozygous Brattleboro rats (DI) have greatly reduced quantities of glycosaminoglycans in the papillary interstitium. Heterozygotes showed staining similar but not identical to that of normal rats. The papillary interstitial cells of DI rats lacked the cytoplasmic processes seen in normal rats, and the normal relationship of these cells to the tubular elements of the papilla was absent. Electron microscopy revealed that the papillary interstitial cells of DI rats appeared less active than those of heterozygous or normal rats. In DI rats these cells displayed reduced numbers of lipid droplets and mitochondria, and the Golgi apparatus and rough endoplasmic reticulum were poorly developed. The altered ultrastructure of the papillary interstitial cells may be responsible for the reduction of interstitial glycosaminoglycans in DI rats. Glycosaminoglycans possess properties which may contribute to urinary concentration. It is suggested that the interstitial tissue of the renal papilla is influenced by antidiuretic hormone.     

Experimental renal papillary necrosis in the rat: The selective vulnerability of medullary structures to injury

Summary Acute renal papillary necrosis was produced in rats by the administration of ethyleneimine. Low doses resulted in necrosis of interstitial cells, thin limbs of the loops of Henle and vasa recta, while collecting ducts were spared (subtotal renal papillary necrosis). High doses resulted in necrosis of all elements of the papilla (total renal papillary necrosis). Although the ranges of the doses that produced these two patterns of necrosis overlapped, it is clear that there is a dose dependent selective vulnerability of renal medullary structures to injury by the toxic agent studied.     

Glycosaminoglycans of the rat renomedullary interstitium: ultrastructural and biochemical observations

The rat renal papillary interstitum which contains abundant proteoglycans is a unique area important in renal function. These proteoglycans were studied ultrastructurally by ruthenium red fixation and staining and phosphate-buffered fixation before and after enzyme digestion. A tissue culture of rat renomedullary interstitial cells, the predominant cell of the renal papillary interstitum, was studied for its ability to synthesize proteoglycans and the proteoglycans were then analyzed. Tissue slices of whole rat renal inner medulla were also evaluated for their synthetic ability. In combination, these studies indicate that the dominant glycosaminoglycan is hyaluronic acid. The tissue culture of rat renal medullary interstitial cells synthesized glycosaminoglycans and on analysis, hyaluronic acid was found to be the chief glycosaminoglycan secreted by the renomedullary interstitial cells. Combined with the removal of the proteoglycans from tissue by leech hyaluronidase and testicular hyaluronidase, this suggests that the dominant glycosaminoglycan is hyaluronic acid. Hyaluronic acid is also synthesized by the intact papilla confirming the findings with the tissue culture. However, in addition, sulfated glycosaminoglycans were also synthesized by the intact papilla, presumably the product of the noninterstitial components of the papilla.     

Experimental folic acid nephropathy

In rats, single intravenous doses of folic acid induce damage to renal tubular epithelium, deposition of folic acid in tubular lumens, increase in wet kidney weight, oliguria and interstitial connective tissue proliferation. Separation of the nephrotoxic and obstructive effects of folic acid was attempted by pretreatment with NH4Cl or NaHCO3. These effects of folic acid were unaltered by pretreatment with NH4Cl and there was, in addition, accumulation of eosinophilic droplets in papillary collecting duct epithelium. After pretreatment with NaHCO3, folic acid deposition is decreased or absent; there is a smaller increase in wet kidney weight; the rats are polyuric rather than oliguric; interstitial connective tissue proliferation is reduced; and no droplets form in papillary collecting ducts, but lesions are still present in proximal convoluted tubule epithelial cells. These findings indicate that folic acid has direct nephrotoxic effects independent of intraluminal folic acid deposition, and that damage to renal epithelium, unlike that induced by many nephrotoxins, occurs at several levels of the nephron.     

Early pathophysiological features in canine renal papillary necrosis induced by nefiracetam

To ascertain the early pathophysiological features in canine renal papillary necrosis (RPN) caused by the neurotransmission enhancer nefiracetam, male beagle dogs were orally administered nefiracetam at 300 mg/kg/day for 4 to 7 weeks in comparison with ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), at 50 mg/kg/day for 5 weeks. During the dosing period, the animals were periodically subjected to laboratory tests, light-microscopic, immunohistochemical, and electron-microscopic examinations and/or cyclooxygenase (COX)-2 mRNA analysis. In laboratory tests, a decrease in urinary osmotic pressure and increases in urine volume and urinary lactate dehydrogenase (LDH) level were early biomarkers for detecting RPN. Light-microscopically, nefiracetam revealed epithelial swelling and degeneration in the papillary ducts in week 7, while ibuprofen displayed degeneration and necrosis in the papillary interstitium in week 5. In immunohistochemical staining with COX-2 antibody, nefiracetam elicited a positive reaction within interstitial cells around the affected epithelial cells in the papillary ducts (upper papilla) in week 7, and ibuprofen positively reacted within interstitial cells adjacent to the degenerative and/or necrotic lesions in week 5. Ultrastructurally, nefiracetam exhibited reductions of intracellular interdigitation and infoldings of epithelial cells in the papillary ducts, whereas ibuprofen showed no changes in the identical portions. Thus, the early morphological change in the papilla brought about by nefiracetam was quite different from that elicited by ibuprofen. By the renal papillary COX-2 mRNA expression analysis, nefiracetam exceedingly decreased its expression in week 4, but markedly increased it in week 7, suggesting an induction of COX-2 mRNA by renal papillary lesions. These results demonstrate that the epithelial cell in the papillary ducts is the primary target site for the onset of RPN evoked by nefiracetam.     

Differential expression of heat shock protein 27 and 70 in renal papillary collecting duct and interstitial cells – implications for urea resistance

The adaptation of renal medullary cells to their hyperosmotic environment involves the accumulation of compatible organic osmolytes and the enhanced synthesis of heat shock proteins (HSP) 27 and 70. While the mechanisms leading to osmolyte accumulation are similar in papillary collecting duct (PCD) and papillary interstitial (PI) cells, the present data demonstrate that HSP27 and HSP70 are expressed differentially in these cells both in vivo and in vitro . HSP70 is abundant in PCD, but not expressed in PI cells in the papilla in situ , while HSP27 is expressed in both PCD and PI cells. These observations could be reproduced by non-permeant solutes in cultured cells. Osmotic stress strongly induced HSP70 in MDCK cells (as a model for PCD cells), but not in PI cells, while HSP27 was constitutively expressed in MDCK cells and was up-regulated in PI cells. Since prior hypertonic stress (NaCl addition) protects MDCK against subsequent exposure to high urea concentrations, this effect was also assessed in PI cells. In both cell lines, hypertonic pretreatment prior to urea exposure (400 m m ) strongly attenuated caspase-3 activation. Inhibition of HSP27 expression by antisense transfection diminished the protective effect of hypertonic preconditioning in PI cells, while attenuation of HSP70 expression in MDCK cells diminished the protective effect of hypertonic preconditioning in these cells. These observations indicate that PCD and PI cells employ cell-specific mechanisms for protection against high urea concentrations as present in the renal papilla during antidiuresis.     

Ultrastructural appearances of acute renal papillary lesions induced by aspirin

Renal papillary necrosis develops 16 hr after intravenous administration of aspirin to the uninephrectomised homozygous Gunn rat. Ultrastructural studies show the papillary interstitial cells to be most severely affected, the first changes being visible at 1 hr. Changes in capillaries are late in onset, and this suggests that the lesions are due to a direct toxic effect rather than to ischaemia.     

Effect of dehydration on the interstitial cells of the renal papilla

The population of interstitial cells at the base of the renal papilla of the albino ra⁺ consists of cells of two types which differ in the degree of development of the endoplasmic reticulum. In intact rats, cells with a weakly developed reticulum predominate. Dehydrated animals are characterized by cells with a well-developed reticulum. It is submitted that the main function of the interstitial cells is connected with the activity of the granular endoplasmic reticulum.Laboratory of Histophysiology, Institute of Physiology, Siberian Branch, Academy of Medical Sciences of the USSR, Novosibirsk. (Presented by Academician of the Academy of Medical Sciences of the USSR V. P. Kaznacheev.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 86, No. 9, pp. 262–264, September, 1978.     

Irreversible damage to the medullary interstitium in experimental analgesic nephropathy in F344 rats

Renal papillary necrosis (RPN) and a decreased urinary concentrating ability developed during continuous long-term treatment with aspirin and paracetamol in female Fischer 344 rats. Renal structure and concentrating ability were examined after a recovery period of up to 18 weeks, when no analgesics were given, to investigate whether the analgesic-induced changes were reversible. There was no evidence of repair to the damaged medullary interstitial matrix, or proliferation of remaining undamaged type 1 medullary interstitial cells after the recovery period following analgesic treatment. The recovery of urinary concentrating ability was related to the length of analgesic treatment and the extent of the resulting inner medullary structural damage. During the early stages of analgesic treatment, the changes in urinary concentrating ability were reversible, but after prolonged analgesic treatment, maximum urinary concentrating ability failed to recover. This study shows that prolonged analgesic treatment in Fischer 344 rats causes progressive and irreversible damage to the interstitial matrix and type 1 interstitial cells leading to RPN. The associated urinary concentrating defect is reversible only during the early stages of structural damage to the inner medulla.     

Splenic lymphangioma with papillary endothelial proliferation: a case report and review of the literature

A 76-year-old man complained of difficulty breathing. A solitary mass was found in the spleen by ultrasonography and the tumor was excised. Grossly, the tumor was 3.9 x 2.9 cm in size, solid and brownish in color. A stellate scar-like fibrosis was observed in the center of the tumor. Histologically, the tumor consisted of the proliferation of irregular and small lymph vessel-like spaces, with sclerotic change in the center. The lymph vessel-like spaces showed papillary projections of the lining cells. The lumen contained amorphous proteinaceous fluid. Immunohistochemically, the lining cells of lymph vessel-like spaces were positive for endothelial markers (CD31, CD34, factor VIII-related antigen), and bound Ulex europaeus agglutinin-1. The tumor was diagnosed as splenic lymphangioma, but its appearance was rather unusual for a typical splenic lymphangioma because of the presence of papillary endothelial proliferation and scar-like fibrosis. Splenic lymphangioma with papillary endothelial proliferation is uncommon, and there have been only four cases reported.     

A mast cell secretagogue, compound 48/80, prevents the accumulation of hyaluronan in lung tissue injured by ionizing irradiation

Irradiation with a single dose of 30 Grey on the basal regions of the lungs of Sprague-Dawley rats induced a peribronchial and alveolar inflammation. Infiltration of mast cells in the edematous alveolar interstitial tissue and also in the peribronchial tissue were characteristic features of the lesion. The appearance of mast cells was already seen 4 wk after irradiation and by weeks 6 to 8 there was a heavy infiltration. The staining properties suggested that they were connective tissue-type mast cells. The infiltration of mast cells was paralleled by an accumulation of hyaluronan (hyaluronic acid) in the alveolar interstitial tissue 6 and 8 wk after irradiation. The recovery of hyaluronan (HA) during bronchoalveolar lavage (BAL) of the lungs also increased at this time. Treatment with a mast cell secretagogue, compound 48/80, induced a distinct reduction of granulated mast cells in the alveolar tissue. Regular treatment with compound 48/80 from the time of irradiation considerably reduced the HA recovery during BAL and the HA accumulation in the interstitial tissue but did not affect the interstitial infiltration of mononuclear cells and polymorphonuclear leukocytes. By contrast, an accumulation of HA in the alveolar interstitial space was induced when compound 48/80 was given not until mast cell infiltration of the lung had started. The effects of compound 48/80 indicate that the connective tissue response after lung irradiation is dependent on whether or not mast cell degranulation is induced before or after the mast cell infiltration of the alveolar tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular epithelial cell lesions in rat renal isografts

Visceral glomerular epithelial cell lesions--microvillus formation, loss of foot processes, osmiophilic inclusion droplets, balloon-like malformation of cell processes, degeneration, necrosis, and loss of cell processes from capillary basement membranes--are found in rat renal isografts 1 mth after transplantation. The lesions, which are most readily recognized in perfusion-fixed material, are essentially focal, affecting neither all glomeruli, nor all cells in any glomerulus, bear no relation to the degree of interstitial nephritis in the graft, and are associated with albuminuria and with focal capillary sclerosis in some glomeruli. They are not restricted to renal isografts but are found in aging rats, in different experimental models of glomerular disease and in clinical glomerular disorders, again in association with proteinuria and glomerulosclerosis. It is therefore proposed that glomerular epithelial cell damage increases capillary permeability and impairs maintenance of the integrity of the capillary wall, leading to proteinuria and focal glomerulosclerosis.     

Inner-medullary organic osmolytes and inorganic electrolytes in K depletion

The renal concentrating defect typical for chronic K depletion has been ascribed to malfunction of renomedullary cells caused by inadequate accumulation of organic osmolytes. A reduction in intracellular ionic strength, which is believed to influence decisively the accumulation of organic osmolytes, has been held responsible for insufficient osmolyte accumulation. To test this hypothesis, intra- and extracellular Na, Cl and K concentrations, the major determinants of ionic strength, were measured in the papilla by electron microprobe analysis and organic osmolytes (glycerophosphorylcholine, betaine, sorbitol, myo-inositol, free amino acids) in inner-medullary tissue by HPLC in antidiuretic rats kept on either a control (normal-K) or a K-deplete (low-K) diet and in euhydrated rats with free access to water and control diet. K depletion was associated with a reduced urine concentrating ability. Papillary interstitial ionic strength (sum of Na, Cl and K) in antidiuretic low-K rats was significantly reduced compared with antidiuretic normal-K rats (688+/-19 vs. 971+/-61 mmol/kg wet wt) but was similar to that in euhydrated normal-K rats (643+/-35 mmol/kg wet wt). The lower interstitial ionic strength in antidiuretic low-K and euhydrated normal-K rats was associated with a lower total content of organic osmolytes in the inner medulla (365+/-14 and 381+/-20, respectively, vs. 465+/-11 mmol/kg protein in antidiuretic normal-K rats). Intracellular ionic strength (sum of Na, Cl and K) of papillary collecting duct cells, however, was similar in antidiuretic normal-K and euhydrated normal-K rats (171+/-5 and 179+/-11 mmol/kg wet wt) but lower in antidiuretic low-K rats (138+/-9 mmol/kg wet wt). These results do not support the view that, in the steady state of osmotic adaptation of renomedullary cells in situ, intracellular ionic strength is the decisive factor for maintaining high levels of organic osmolytes. During chronic K depletion, reduced osmolyte accumulation by renomedullary cells may be the consequence, rather than the cause, of lower medullary interstitial tonicity.     

Mast cells in the human carotid body.

Mast cell counts were carried out on sections of human carotid bodies from 39 subjects showing one of four stages of histological change associated with aging, and in five subjects showing different forms of histopathology in the carotid body associated with disease. There was no relation between mast cell density and age or the histological changes associated with aging of glomic tissue. The normal range of mast cell density calculated in terms of the 80% confidence limits was 18.5 to 67.5/mm2. In three middle aged subjects with carotid bodies of normal histological appearance there was an abnormally high density of 83 to 96/mm2. In two elderly subjects showing age changes of fibrosis and accumulation of lymphocytes there was an abnormally low density of 12/mm2 or less. Mast cell density was not related to different types of carotid body hyperplasia. The mast cells were essentially stromal in location, usually closely applied to the walls of small glomic blood vessels, and were rarely found in intimate association with glomic chief cells. This suggests that mast cells are not directly concerned with the functions of glomic cells but does not preclude the possibility that they may have some effect on regulating glomic blood vessels and thus participate in the distribution of blood supply within the carotid body.     

Transmission electron microscopic and immunohistochemical observations of resting follicles of feathers in chicken show massive cell degeneration

The molting cycle of feathers includes an anagen (growth) stage, a likely catagen stage where the feather follicles degenerate, and a resting stage where fully grown feathers remain in their follicles and are functional before molting. However, the cytological changes involved in the resting and molting stages are poorly known, so the results of an ultrastructural analysis of these processes in adult chick feathers are presented here. The study showed that the dermal papilla shrinks, and numerous cells present increased heterochromatin and free collagen fibrils in the extracellular matrix. Degeneration of the germinal epithelium of the follicle—the papillary collar—occurs with an initial substantial contraction of cells followed by an increase in heterochromatin, vesicle and lipid accumulation, and membrane and organelle degeneration. Desmosomes are still present between degenerating epithelial cells, but ribosomes and tonofilaments disappear. This suggests that cell necrosis initially proceeds as a major contraction resembling apoptosis—a process termed necroptosis, which was previously also shown to occur during the formation of barbs and barbules in mature down and pennaceous feathers. This study suggests that, aside from apoptosis, the collar epithelium degenerates due to external factors, in particular the retraction of blood vessels supplying the dermal papilla. In contrast, revascularization of the dermal papilla triggers a new phase of feather growth (anagen).     

Changes of sodium and urea concentrations in the renal papillary interstitial fluid on dehydration of rats

1. The isolated renal papillae of a rat were centrifuged in a two tube assembly which allowed fluid from the tissue to separate into the lower tube.2. The papillae were centrifuged for 15 min at 300 g and 1500 g consecutively.3. After intraperitoneal injection of Na (131)I-diatrizoate, the activities of urine, and fluid samples obtained from the papilla, were compared. It was found at 1500 g that the median value for papillary fluid activity was 1.52% of the activity of urine. This is evidence that the papillary fluid was virtually free from any contamination from the terminal collecting ducts.4. It is considered that the fluid sample obtained from the papillae by centrifugation at 1500 g is a representative and reproducible sample of interstitial fluid.5. The method was used to demonstrate changes in solute concentrations in the renal papillary fluid, following dehydration of rats.     

Scanning electron microscope studies of the papilla basilaris of some turtles and snakes

The papillae basilares of three species of turtles and four species of snakes were studied by SEM. The papillae of turtles are relatively large among reptiles and are characterized by a long, horizontal middle section resting on a wide basilar membrane. Both terminal ends of the papilla extend onto the surrounding limbus in the form of a forked or “T”-shaped end or as a curved, “hook”-like process. Details vary with the species. In the three species of turtles studied, there were between 1,100 and 1,400 hair cells on a papilla. The tectorial membrane covering the horizontal portion of the papilla is heavy in appearance and tightly attached to the kinocilial bulbs. The terminal ends of the papilla are covered by a thin gelatinous material. In addition, a mat-like tectorial network covers the supporting cells and extends from the microvilli of the supporting cells to the overlying tectorial membrane. All hair cells are unidirectionally and abneurally oriented. The supporting cell surfaces form a large part of the papilla and, thus, hair cell density is low. The papillae of the two boid snake species studied are moderately long among snakes and contain a moderate number of hair cells (574 in Epicrates and 710–780 in Constrictor). Papillar form is elongate, ovoid, or canoe-shaped. The tectorial membrane may be either highly fenestrated or moderately dense and covers all but a few of the terminal hair cells. A tectorial-like mat covers all but a few of the terminal hair cells. Most hair cells are unidirectionally and abneurally oriented. A few terminal cells in boids may show reverse orientation. Hair cell density is similar to that of turtles.     

The induction of renal papillary necrosis in Gunn rats by analgesics and analgesic mixtures.

Homozygous members of the mutant Gunn strain of Wistar rats genetically lack the enzyme uridine diphosphate glucuronyl transferase. "High" and "low" dose gavage feeding for 18-34 days of an analgesic mixture containing aspirin, phenacetin and caffeine (APC) confirmed the previously reported susceptibility of these animals to analgesic induced renal papillary necrosis. Heterozygotes do not share the gross enzyme deficiency of homozygotes and, when treated with APC under identical conditions, failed to develop renal papillary necrosis. Groups of homozygotes were dosed by gavage with aspirin, phenacetin and paracetamol for 4 weeks. Renal papillary necrosis was produced by all 3 drugs, the lowest frequency of lesions occurring with phenacetin. It is postulated that the enzyme deficiency of homozygous Gunn rats influences the metabolism of analgesics to favour the excretion of nephrotoxic metabolites. The renal papillary necrosis appearing in these experiments is essentially an acute lesion, differing both in natural history and morphology from the renal papillary necrosis of analgesic nephropathy, suggesting that the pathogeneses of the experimental and human lesions differ.