Anti-inflammatory drugs and renal papillary necrosis

The literature on renal papillary necrosis (RPN) associated with the administration of non-steroidal antiinflammatory drugs (NSAID) to rats and man, is reviewed. RPN is almost universally reported after long term administration of NSAID to rats, reports being cited for an indomethacin analog, phenylbutazone, fenamic acids, fenoprofen and sudoxicam. Aspirin will also induce RPN in rats, and is probably the cause of the ‘analgesic nephropathy’ linked to abuse of aspirin/phenacetin combinations in man. RPN is reported at autopsy in human arthritics, but whether this is a facet of the disease, or of long term salicylate ingestion, is not clear. NSAID are rarely implicated in RPN in humans.     

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.     

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.     

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.     

Mechanism of renal necrosis induced by bromobenzene or chlorobenzene

Treatment of mice or rats with a single intraperitoneal dose of [¹⁴C]-bromobenzene or [¹⁴C]-chlorobenzene produced necrosis of the proximal convoluted renal tubules within 24–48 hr. The development of renal necrosis was associated with the covalent binding of substantial amounts of radiolabeled material to kidney proteins, and autoradiograms revealed that most of the covalently bound material was localized within the necrotic tubular cells. Prior inhibition of [¹⁴C]-bromobenzene metabolism in vivo with piperonyl butoxide blocked both the necrosis and the binding, suggesting that the necrosis and binding are caused by a toxic metabolite. Studies on the metabolism and covalent binding of [¹⁴C]-bromobenzene in hepatic and renal microsomes in vitro were compatible with the interpretation that the renal necrosis was caused by a metabolite formed in the liver and transported by the circulation to binding sites in the renal tubules.     

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.     

具有透明细胞乳头状肾细胞癌形态特征的透明细胞性肾细胞癌的临床病理特征

目的探讨具有透明细胞乳头状肾细胞癌形态特征的透明细胞性肾细胞癌(clear cell papillary renal cell carcinoma-like clear cell renal carcinoma, CCPRCC-like CCRCC)的临床和病理特征, 旨在提高对该类肿瘤的认识。方法回顾性分析浙江大学医学院附属第一医院诊断的3例CCPRCC-like CCRCC的临床资料、组织学形态及免疫表型, 随访患者预后并复习相关文献。结果男性2例, 女性1例, 平均年龄43岁。肿块最大径9 cm。镜下观察3例病例均包含透明细胞乳头状肾细胞癌样(CCPRCC-like)及透明细胞性肾细胞癌样(CCRCC-like)两种区域, 前者在整个瘤体所占比例为20%～90%。CCPRCC-like区域含有囊、乳头、腺管状结构。细胞核远离基底膜, 细胞核WHO/国际泌尿病理协会(ISUP)分级1级。在CCPRCC-like区域, 细胞角蛋白(CK)7表达范围10%～80%, 中等及以上强度表达。CD10表达均为100%, 主要为顶端胞膜表达。在CCRCC-like区域, 1例CK7阴性, 其余...     

New features of renal lesion induced by stroma free hemoglobin

This study focused on the subacute renal lesions resulting from the infusion of stroma free hemoglobin (SFH), which remains under evaluation as a potential blood substitute despite limited renal toxicity observed in acute infusion. Four groups of rats received different doses of SFH (0.03, 0.48, 0.96, and 1.46 g, respectively) and were monitored, on alternate days, for their glomerular filtration rate over the course of 10 days. Another group of 6 rats receiving 0.96 g SFH was sacrificed at day 10 for examination of renal morphology. The low dose (0.03 g) of SFH infusion did not alter the creatinine clearance (Clcr) over 10 days. The Clcr decreased in rats receiving 0.48 g SFH but fully recovered at day 10. A persistent decrease in Clcr was observed in the groups of rats receiving 0.96 and 1.68 g of SFH. Tubular necrosis was the most prominent renal lesion distributed in the proximal tubules, especially in the convoluted segment of the juxtamedullary nephrons. Pearls' stained cytoplasmic granules and electron-dense lysosomal granules were found in surviving proximal tubules. Necrosis was the predominant mechanism of cell death. This study revealed for the first time proliferation of smooth endoplasmic reticulum in the proximal tubules after SFH treatment, where it appeared as nodular aggregates of tubulovesicular structures. The effect of SFH on the proximal tubule appeared to be a direct toxicity, and this toxicity was shown to be dose dependent. The presence of reversible toxicity indicated that a safety limit dosage for SFH infusion exists and that tolerance dose of SFH can be determined for clinical applications.     

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.     

Cytohistopathologic hybrid renal cell carcinoma with papillary and clear cell features

Clear cell (CRCC) and papillary (PRCC) renal cell carcinomas (RCC) are the two most frequent subtypes of RCC. In this study, we studied RCC which displayed a hybrid morphology with areas of PRCC and CRCC or which contained papillary structures with clear cell changes (CCC).

Consecutive cases of RCC collected over a 12-year period were reviewed to identify RCC with papillary structures and a possible admixture between CRCC and non-oncocytic PRCC. Special stains for glycogen and immunostaining for cytokeratin 7 were applied to sections containing both areas of classical PRCC and PRCC with CCC.

Of the total of 541 RCC retrieved, there were 68 non-oncocytic RCC having papillary structures that could be grouped into: (a) group 1 (15 cases), CRCC with areas of papillary formation; (b) group 2a (9 cases), PRCC with extensive CCC with areas of foamy epithelial cells or macrophages; (c) group 2b (18 cases), RCC with areas of classical PRCC with focal CCC; and (d) group 3 (26 cases), RCC with features of groups 2a and 2b and containing areas of classical CRCC. There was a high rate (12/68) of sarcomatous transformation in the study cases. Groups 2 and 3 were associated with a higher rate of vascular invasion, distant metastasis, and mortality than classical PRCC and a higher rate of lymph node metastasis than CRCC.

Our study identifies two groups of RCC (referred to as groups 2 and 3) that exhibit characteristic cytohistopathologic hybrid features that set them apart from classical RCC. This type of hybrid tumor seems to be associated with a more aggressive biologic behavior, and its recognition may facilitate the classification of RCC with ambiguous morphology.     

Numerical chromosomal aberrations in papillary renal cortical tumors: relationship with histopathologic features

Previous studies have indicated that a combined trisomy of chromosomes 7 and 17 is a constant finding in papillary renal cortical adenomas and that papillary renal cell carcinomas are marked by additional trisomies such as trisomy 12, 16, and 20. The aim of our study was to compare this cytogenetic classification of papillary renal cortical tumors with conventional histopathologic classification. We performed interphase cytogenetics with enumeration probes for chromosomes 7, 12, 16, 17, and 20 on 41 papillary tumors found in 21 nephrectomy and 10 autopsy kidneys. A total of 38 tumors harbored gains of chromosomes 7 or 17, and most of these showed a trisomic signal distribution. The three tumors with normal copy numbers for chromosomes 7 and 17 were a papillary grade-2 carcinoma, a small adenoma (both with distinctive oxyphilic cytoplasm), and a papillary carcinoma with focally clear cells. Gains for chromosomes 12, 16, or 20 were found in 21 tumors and were significantly associated with the presence of histologic criteria of malignancy ( P<0.0001). Histopathologic and cytogenetic features of malignancy were found in eight tumors smaller than 10 mm. There is a good agreement of cytogenetic and histopathologic criteria of malignancy in papillary renal cell tumors. Interphase cytogenetics might give useful additional information in cases of doubt or when only small biopsy specimens are available.     

Healed experimental renal papillary necrosis and cortical scarring in the rat from 2-bromoethylamine hydrobromide

Summary Male Sprague-Dawley rats were each given a single subcutaneous injection of an aqueous solution of bromoethylamine hydrobromide (BEA) at dose levels of 80 mg/kg (16 rats), 125 mg/kg (15 rats) and 250 mg/kg (16 rats) or a single subcutaneous injection of water (controls, 15 rats). The dose levels were chosen so as to cause renal papillary injury varying from minor necrotic foci to necrosis and subsequent sloughing of the entire papilla. The animals were killed after 5 months and the kidneys were weighed and examined macroscopically and microscopically for the presence of RPN and cortical scarring. Macroscopically evident RPN occurred in 18 of 43 surviving BEA-treated rats, bilaterally in 16 and unilaterally in 2. Bilateral asymmetry of the extent of sloughing was evident. All kidneys with macroscopic RPN exhibited cortical scarring. Asymmetry of the extent of atrophy and scarring in some animals resulted in a significant unilateral reduction in renal weight and a significant contralateral compensatory hypertrophy. Twenty-three of the 25 BEA-treated rats without macroscopically evident RPN exhibited minor, histologically visible lesions of the renal papillae including necrosis of loops of Henle in the presence of intact collecting ducts. Only 2 of these animals exhibited tiny, unilateral cortical scars, and renal weights did not differ significantly from those of controls. It may therefore be concluded, contrary to certain published proposals: that experimental RPN may be followed by severe renal cortical scarring, reduction in renal size and (in the presence of asymmetrical lesions) compensatory renal hypertrophy, and that necrosis of thin limbs of loops of Henle does not appear to lead to frequent or severe cortical scarring.