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.     

Presence and extent of histological tumour necrosis is an adverse prognostic factor in papillary type 1 but not in papillary type 2 renal cell carcinoma

Aims: To date, only limited information is available on the prognostic significance of the presence and extent of histological tumour necrosis with regard to papillary renal cell carcinoma (RCC) types 1 and 2 subclassification. Thus, the aim of this study was to evaluate the prognostic impact of these pathological features on the clinical outcome in papillary subtypes. Methods and results: The influence of histological tumour necrosis on the clinical outcome in 177 patients with papillary RCC was evaluated. For papillary subtype 1, the presence of histological tumour necrosis was an independent negative prognostic factor for disease‐free survival (P = 0.039), and a greater extent of necrosis (>20%) was significantly associated with both poor disease‐free and overall survival (P = 0.033 and P = 0.041, respectively). Regarding papillary subtype 2, neither the presence nor extent of histological tumour necrosis was a statistically significant negative prognostic factor. Conclusion: Our findings suggest that the presence and extent of histological tumour necrosis are independent prognosticators in papillary RCC subtype 1, but not in papillary subtype 2. Thus, previously reported conflicting data regarding the prognostic impact of tumour necrosis in papillary RCC might be explained, in part, by heterogeneous subtypes.     

Experimental Papillary Necrosis of the Kidney: IV. Medullary Plasma Flow

To test the thesis that vasoconstriction plays a significant role in the pathogenesis of papillary necrosis caused by bromoethylamine hydrobromide (BEA), medullary plasma flow was determined in rats treated with BEA. Medullary blood flow was normal ½ to 1 hour after BEA treatment, and was actually elevated 6 hours after BEA. There was no increase in plasma levels of prostaglandins A and E, which would have been expected if there had been medullary ischemia. Pretreatment with reserpine, which inhibited the development of papillary necrosis, had little effect on medullary plasma flow. These observations do not support the notion that vasoconstriction is the mechanism by which BEA causes papillary necrosis.     

Pattern of renal cortical scarring after experimental papillary necrosis

Three types of renal cortical damage were found in rats 2 mth after papillary necrosis had been induced by ethylenimine: (1) Circumscribed areas of interstitial nephritis affecting either deep or superficial nephrons. (2) Wedge-shaped or conical scars, extending from capsule to inner medulla. (3) Widespread tubular dilatation and cyst formation with a diffuse increase in interstitial tissue, usually associated with dense fibrous repair of the papillary remnant. The extent and character of the cortical changes did not appear to be determined by the severity of the papillary necrosis, and even the more severe cortical lesions were not accompanied by any major reduction in kidney size. Although these chronic experimental cortical lesions are the products of a less complex and less protracted natural history than end stage cortical damage in analgesic nephropathy, some of the factors influencing their evolution, such as infection, may also determine the natural history of the clinical lesion.     

Differentiated papillary kidney tumors. Differentiation between metanephric adenoma and papillary adenoma

Metanephric adenoma of the kidney is a well described tumor entity. The differential diagnosis between papillary adenoma or papillary carcinoma type 1 and metanephric adenoma of the kidney can be challenging in single cases. We report two cases of metanephric adenomas and compare their immunophenotype with a papillary adenoma. The analysis of these metanephric adenomas and a review of the literature shows that CD-57 positivity and lack of EMA expression are helpful in distinguishing metanephric adenoma from papillary adenoma and papillary carcinoma. Glomeruloid structures, Psammoma bodies, necrosis or expression of cytokeratin 7 and vimentin are common features in metanephric adenoma and papillary adenoma or papillary carcinoma. The knowledge of the immunohistochemical constellation is important, because metanephric adenoma can be very large and often have some necrosis.     

Immunohistochemical staining of papillary breast lesions.

The separation of ductal papilloma from intraductal papillary carcinoma of the breast on hematoxylin and eosin stained sections often presents diagnostic difficulty. Immunohistochemical staining is often employed in diagnosis, historically with smooth muscle actin (SMA). In this study, the staining characteristics of a panel of myoepithelial markers (calponin, p63, P-cadherin), were compared with SMA, and the epithelial expression of CD44s was assessed in 99 papillary lesions. SMA, calponin, and p63 demonstrated myoepithelial cells in 61%, 63%, and 65% of papillary lesions, respectively. However, specificity was quite variable. Calponin-stained stromal myofibroblasts (35% of cases), vessel pericytes (92%), and endothelial cells (69%), though each to a lesser degree than SMA. Calponin also showed cross reactivity with epithelium in 18% of cases. p63 was almost completely restricted to myoepithelial cell nuclei, and did not stain vascular smooth muscle or myofibroblasts. However, p63 stained the epithelial component in one papillary carcinoma, a basal layer of cells in 1 biphasic invasive carcinoma, and the cytoplasm in 1 case. P-cadherin stained both epithelial and myoepithelial cells. The epithelial expression of CD44s and did not distinguish papillomas from papillary carcinomas. Thus, P-cadherin and CD44s are not useful in the characterization of papillary lesions. Given increased specificity as compared with SMA, the combination of p63 and calponin is recommended for analysis of breast papillary lesions.     

Correlation of nuclear morphometry with pathologic parameters in ductal carcinoma in situ of the breast.

Morphometric features of nuclear perimeter, nuclear area, feret ratio, and feret circle were studied in a series of 64 cases of ductal carcinoma in situ (DCIS) of the breast in Singapore women. The results were compared with pathologic parameters of tumor size, nuclear grade, necrosis, cell polarization, and architectural pattern. There was statistically significant correlation between nuclear perimeter and area with all the pathologic parameters, with the strongest association observed for nuclear grade (P <.0001). Higher grade nuclei as assessed histologically were associated with larger nuclear area (44.14 microm(2) in low-grade lesions, 47.77 microm(2) in intermediate-grade lesions, and 72.05 microm(2) in high-grade lesions) and perimeter (25.94 microm in low-grade nuclei, 27.12 microm in intermediate-grade nuclei, and 33.66 microm in high-grade nuclei). DCIS lesions with necrosis and absence of polarization also revealed increased nuclear area and perimeter (P <.05). Comedo architecture was associated with larger nuclear area and perimeter (65.97 microm(2), 31.7 microm) than the papillary subtype (42.17 microm(2), 25.29 microm), with the mixed morphologic pattern disclosing intermediate values (54.83 microm(2), 29.43 microm). There was direct correlation for tumor size with nuclear area and perimeter (P <.01). No similar relationship was found between pathologic parameters and feret ratio or circle, indicating that nuclear roundness or lack of it did not factor as a significant component in the pathologic assessment.     

Papillary necrosis in experimental renal transplantation in the rat

Renal papillary necrosis is a frequent complication of unsuccessful renal transplantation in rats, occurring in both isografts and allografts. Papillary necrosis does not occur alone, but only and inevitably in association with severe cortical damage. The pattern of the lesion is different from other forms of papillary necrosis in that the least severe lesions occur in the outer medulla and the more severe lesions involve both medulla and papilla. The incidence of papillary necrosis is increased in isografts, but not in allografts, by longer preservation times. It is suggested that the principal underlying cause may be damage to medullary capillaries, occurring either during preservation or as a consequence of rejection and leading to medullary ischemia.     

Haloalkylamine-induced renal papillary necrosis: a histopathological study of structure-activity relationships.

The haloalkylamine 2-bromoethanamine (BEA) causes necrosis of renal papillae of rats within 24 h of a single intraperitoneal dose greater than or equal to 100 mg/kg. Nine structural analogues of BEA, differing by halide substitution, alkyl chain elongation or amine substitution, were tested for their ability to induce renal papillary lesions in rats. Three compounds (2-chloroethanamine, 3-bromopropanamine and 2-chloro-N,N-dimethylethanamine) induced lesions which were morphologically indistinguishable from those of BEA. All the molecular structural variations investigated reduced papillotoxicity compared with BEA, the parent compound. A variety of non-renal lesions including hepatic, adrenal, testicular and lymphoid necroses were also encountered. The most toxic compound was 2-fluorethanamine, a 5 mg/kg dose of which was lethal and induced renal corticomedullary mineralization and centrilobular hepatic necrosis. One analogue, 3-bromo-2-hydroxypropanamine, caused rapid and extensive necrosis of the adrenal pars fasciculata and reticularis, simulating human Waterhouse Friderichsen syndrome. The three newly identified renal papillotoxins are all theoretically capable of generating direct-acting alkylating species in solution and their activity as direct-acting mutagens in the Ames bacterial mutagenicity test with TA100 (indicating base pair substitution) closely correlated with their potency as papillotoxins. We therefore hypothesize that non-enzymically formed direct-acting alkylating species mediate these papillary lesions, and that the target selectivity of haloalkylamine toxicity most probably results from the accumulation of these alkylating species in papillary tissue.     

Experimental Papillary Necrosis of the Kidney: II. Electron Microscopic and Histochemical Studies

Renal papillary necrosis was induced in rats by bromoethylamine hydrobromide and studied electron microscopically and histochemically. Morphologic changes appear to develop in vessels and tubules simultaneously, rather than tubular lesions preceding and leading to vascular lesions, or vice versa. Abnormalities are recognized as early as 3 hours, but platelets do not make their appearance until 12 hours, eliminating primary vascular thrombosis as the source of papillary injury.     

The effects of chronic papillary necrosis on acid excretion

Complete papillary necrosis in rats can be induced within 1 month following a single injection of 2-bromoethylamine hydrobromide (BEA) (50 mg, i.v.). Utilizing a combination of clearance and balance techniques the effects of complete absence of the papilla was examined as regards urinary acidification, whole kidney glomerular filtration rate (GFR), single nephron GFR, and morphology. Whole kidney GFR was not different from control, however, the percent filtering juxtamedullary nephrons was markedly diminished (87.2±2.1 vs. 31.5±3.6% filtering, control vs. BEA, respectively,P<0.001) and significantly reduced in the superficial nephrons (80.6±3.6 vs. 62.2±6.1% filtering, control vs. BEA, respectively,P<0.05). There was a significant decrease in juxtamedullary single nephron GFR and an increase in the superficial single nephron GFR as assessed by the quantitative Hanssen's technique in the animals with chronic papillary necrosis. Complete papillary necrosis was associated with normal arterial bicarbonate concentration, pH, and plasma electrolyte concentrations. At the same degree of acidemia (induced by NH₄Cl administration) minimal urinary pH, ammonium excretion, and titratable acid excretion were not different than seen in age matched controls. The response to Na₂SO₄ infusion and phosphate infusion was the same in both groups of animals. The urineblood (U-B)pCO₂, an index of urinary acidification, was identical in BEA and control animals. Scanning electron microscopy showed scarring of the juxtamedullary glomeruli one month after BEA. The papilla was sloughed and lying free in the renal pelvis in every experimental animal. These data demonstrate that complete papillary necrosis is not associated with acidosis nor a defect in urinary acidification.     

Papillary cystadenoma of the epididymis. A report of three cases with lectin histochemistry.

Papillary cystadenoma of the epididymis is an uncommon benign tumor associated with von Hippel-Lindau disease. Since metastatic renal cell carcinoma may be histologically similar to papillary cystadenoma, and both are associated with von Hippel-Lindau disease, differentiation between these two entities may be difficult. We performed lectin histochemistry studies on three papillary cystadenomas and compared the results with the staining observed in epididymal ducts, epididymal efferent ductules, and three renal cell carcinomas. Common positive staining was observed following incubation with soybean agglutinin in epididymal ducts and two of the three papillary cystadenomas, while the three renal cell carcinomas did not stain. When epididymal tumors histologically consistent with papillary cystadenoma fail to react with soybean agglutinin, thorough clinical evaluation for an occult renal cell carcinoma should be performed.     

Experimental calcium oxalate nephrolithiasis in the rat. Role of the renal papilla.

Calcium oxalate nephrolithiasis in rats, induced by single intraperitoneal injection of sodium oxalate, is associated with pathologic changes in the renal papillary tip. Calcium oxalate crystals appear in the tubular lumens, in the intercellular spaces between epithelial cells, and attached to the tubular epithelial basal lamina. Unusual paracrystalline structures also develop in the distal tubule associated with the basal lamina. Speculations are made about the role of these structures. The epithelial changes are primarily necrotic and are similar to those described in experimental papillary necrosis. Complete morphologic recovery occurs in 1-2 weeks.     

Glomerular lesions in experimental renal papillary necrosis. I. Ultrastructural aspects and some pathogenic considerations.

Papillary necrosis was induced in rats by a single intravenous injection of bromoethylamine hydrobromide (BEA). From 7 days on glomerular lesions were recognized. They consisted of electron dense deposits mainly subepithelial in location; mild mesangial hypercellularity and matrix increase. Immunofluorescence with anti-rat gammaglobulin was positive, showing granular fluorescence in relation with basement membrane and mesangium. The possibility is raised that these lesions are due to the pathogenic action of immune complexes, the antigen being one arising during the necrosis of the renal papilla. It is also suggested that this mechanism can be operative in ths human being in cases of papillary necrosis of the kidney.     

Unilateral papillary necrosis complicating renal artery stenosis—evidence of activation of the intrarenal renin–angiotensin system?

We report an association between renal artery stenosis and papillary necrosis. We studied three kidneys with renal artery stenosis, two of which showed ipsilateral acute papillary necrosis. In all three cases there had been a sudden fall in perfusion of the ischaemic kidney. In the case with intact papillae, immunostainable renin was normal in amount and distribution, whereas both kidneys with papillary necrosis showed hyperplasia of renin-containing cells, and these were mainly in the JGAs of the juxtamedullary cortex. Since the contralateral kidneys were spared, we suggest that in an ischaemic kidney with hyperplasia of renin-secreting cells in the deep cortex, local activation of the renin-angiotensin system could cause acute papillary necrosis due to vasoconstriction.     

Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas.

Vascular permeability factor (VPF), also known as vascular endothelial growth factor, is a secreted protein implicated in tumor-associated microvascular hyperpermeability and angiogenesis. Tumor cells in 11 of 12 renal cell carcinomas expressed high levels of VPF messenger RNA (mRNA) by in situ hybridization, the only exception being a case of the relatively avascular papillary variant. Expression was further accentuated adjacent to areas of necrosis. Both tumor cells and endothelial cells in small vessels adjacent to tumor stained strongly for VPF protein by immunohistochemistry. Endothelial cells did not express detectable VPF mRNA, but did express high levels of mRNA for the VPF receptors flt-1 and KDR indicating that the endothelial cell staining likely reflects binding of VPF secreted by adjacent tumor cells. Three transitional cell carcinomas also labeled strongly for VPF mRNA. These data suggest an important role for VPF in the vascular biology of these two common human malignancies.     

Drug-induced renal medullary necrosis. II. Mode of calcification in the kidney

Necrosis of the papillary portion of the renal medulla was produced by administration of 2-bromoethylamine hydrobromide in rats. Following the necrosis, calcification develops in the renal medulla adjacent to the necrosed tissue. The calcium deposit is seen in the vesicular bodies about the basement membranes of the tubules and capillaries and in the collagen fibers of the interstitium. These structures such as the vesicular bodies and collagen fibers appear to serve as nucleation sites for dystrophic calcification.     

Platelet-activating factor-induced ischemic bowel necrosis. An investigation of secondary mediators in its pathogenesis.

The authors have previously reported a model of ischemic bowel necrosis produced in the rat by synthetic platelet-activating factor (PAF) or a combination of PAF and bacterial endotoxin. Because rat platelets are refractory to PAF and thromboemboli were not found in the mesenteric or intestinal microvasculature, they suspected that secondary mediators were involved in the pathogenesis of bowel necrosis. They have found the following lipoxygenase products of arachidonic acid, especially leukotrienes (LT), probably played an important role in the pathogenesis of bowel necrosis, because diethylcarbamazine (an inhibitor for LTA synthesis) and FPL55712 (LT antagonist) ameliorated, and at times completely prevented, the lesions. NDGA (a nonspecific lipoxygenase inhibitor) was less effective, probably because of its additional effect on cyclooxygenase inhibition. Verapamil, a calcium channel blocker, ameliorated the disease. Thromboxane A2, a potent vasoconstrictor, was probably not responsible for the ischemia of the gastrointestinal tract. This is suggested by the ineffectiveness of OKY-046 in preventing bowel necrosis. Prostaglandin (PG) E1 infusion often prevented the bowel necrosis, which suggested beneficial effects of vasodilating PGs, probably released as a defense mechanisms. Indomethacin aggravated the disease, probably by inhibiting PG release and shifting the metabolic pathway toward the lipoxygenase pathway. Antihistamine and antiserotonin had no effect, which suggested that these mediators were not involved in the pathogenesis of bowel necrosis. Shock produced by PAF was probably not the only cause of bowel necrosis, because reversal of the hypotension did not always prevent the development of bowel necrosis. Hemoconcentration (increased vasopermeability) and leukopenia induced by PAF did not correlate with the development or severity of bowel necrosis.     

A study on renal papillary necrosis experimentally produced by the Shwartzman mechanism in rabbits

To produce renal papillary necrosis experimentally by means of the Shwartzman mechanism in rabbits, E. coli endotoxin was injected into the renal pelvis unilaterally through the ureter as a preparative procedure after pretreatment by local administration of alcohol, and the same endotoxin was given again 24 hours later, but intravenously this time via the ear vein, as a provocation. Marked necrosis was produced in the renal papillae, where many intravascular fibrin thrombi were found histologically. Such papillary necrosis was largely prevented by heparin administration, and this lesion was considered to be the univisceral Shwartzman reaction occurring in the renal papillae. The lesion produced in the new experimental system of renal papillary necrosis described here has a good similarity to that of human cases in etiology, pathogenesis and morphology. The present system may therefore be a good model of human renal papillary necrosis, and should be useful for future studies.     

Myocardial cell damage during experimental infective endocarditis.

Infective endocarditis was induced in 15 catheterized rabbits by a single intravenous injection of Streptococcus viridans and the papillary muscles from the left ventricle were examined for histologic and ultrastructural changes at 3 and 6 days of infection. Papillary muscles from 10 normal and 12 catheterized uninfected animals were used for comparison. Catheterized animals, infected and uninfected, had cardiac hypertrophy and papillary muscles which showed an increase in myofiber size and some interstitial edema. The muscle from infected hearts had areas of focal necrosis, diffuse monocytic infiltration, and loss of normal myocardial architecture. The papillary muscles from catheterized uninfected animals showed some degree of mitochondrial and sarcotubular swelling as well as contracture of myofibrils; the infected myocardium exhibited dramatic changes in ultrastructure such as mitochondrial swelling and destruction, sarcotubular swelling, separation of the intercalated disc, and myofibrillar contracture and disruption. These histopathologic and ultrastructural changes in papillary muscles from rabbits with bacterial endocarditis are indicative of the presence of myocardial cell damage.