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.     

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.     

Chronic renal lesions in the uninephrectomized Gunn rat after analgesic mixtures

Chronic cortical and medullary damage have been produced in uninephrectomized homozygous Gunn rats by single doses of the analgesics aspirin, paracetamol and phenazone, and by analgesic mixtures. The lesions are more severe than those of other experimental models of analgesic nephropathy, and the appearances of the cortical lesions suggest that they are ultimately due to the effects of papillary necrosis rather than to acute tubular necrosis observed in acute experiments with this model. The presence of an acute inflammatory reaction in both cortex and medulla in a number of animals one month after administration of analgesics indicates the possibility that the observed chronic renal damage may result from the intervention of additional complicating factors rather than from a single direct effect of analgesics.     

Biomarkers of collecting duct injury in Han-Wistar and Sprague-Dawley rats treated with N-phenylanthranilic Acid

N-phenylanthranilic acid is a chloride channel blocker that causes renal papillary necrosis in rats. Studies were conducted in two strains of male rats to evaluate novel biomarkers of nephrotoxicity. Han-Wistar rats were given daily oral doses of 50, 350, or up to 700 mg/kg/day of NPAA, and Sprague-Dawley rats were given 50 or 400 mg/kg/day of NPAA. Rats were euthanized on days 8 and 15. The candidate kidney injury biomarkers renal papillary antigen-1 (RPA-1, for collecting duct injury), clusterin (for general kidney injury), α-glutathione-S-transferase (a proximal tubular marker), and μ-glutathione-S-transferase (a distal tubular marker) were measured in urine by enzyme immunoassay. Characteristic degeneration and necrosis of the collecting duct and renal papilla were observed in Han-Wistar rats at the high dose on day 8 and at the mid and high doses on day 15, and in Sprague-Dawley rats given the high dose on days 8 and 15. Increases in urinary RPA-1, and to a lesser extent urine clusterin, were generally associated with the presence of collecting duct injury and were more sensitive than BUN and serum creatinine. On the other hand, decreases in α-glutathione-S-transferase without proximal tubule lesions in both strains and decreases in μ-glutathione-S-transferase in Sprague-Dawley rats only were not associated with morphological proximal or distal tubule abnormalities, so both were of less utility. It was concluded that RPA-1 is a new biomarker with utility in the detection of collecting duct injury in papillary necrosis in male rats.     

Renal toxicity of non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs represent the most heavily prescribed and used class of drugs in human medicine. Most are derivatives of either salicylates, propionic acid, indoleacetic acid, anthranilic acid, pyrazolone, or oxicams. They depress the synthesis of prostaglandins from arachidonic acid by reversible inhibition of the enzyme cyclooxygenase. In the kidney, prostaglandins PGE2 and PGI2 modulate the vasoconstrictor effects of angiotensin II, norepinephrine, and vasopressin. In the presence of volume contraction, anesthesia, or disease states associated with high levels of these hormones, prostaglandins regulate glomerular filtration, vascular resistance, and renin secretion. They additionally influence urine volume and sodium content. In man, a syndrome of analgesic abuse that has been identified worldwide occurs more frequently in females than males and can result in severe renal damage, most notably renal papillary necrosis. Most common laboratory animals are relatively resistant to developing the renal lesion associated with NSAIDs unless high doses are given over long periods of time and some withholding of water is introduced into the protocol. Diuresis with 5% dextrose and water is protective. Studies of paracetamol and salicylate have demonstrated that these compounds concentrate in the papillary tip of the kidney at concentrations of 4 to 13 times the plasma levels in dogs and rabbits, respectively. Renal papillary necrosis has been described in horses on maintenance doses of phenylbutazone where dehydration or reduced water consumption has occurred. The lesion can be reproduced experimentally if water is withheld during a portion of the dosing interval. An increased incidence of uroepithelial tumors have been reported in patients with a history of analgesic abuse.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Effects of lysine and other amino acids on kidney structure and function in the rat.

Lysine is a major constituent of amino acid parenteral nutrition solutions which have recently been shown to increase the severity of various types of acute renal failure in the rat. In previous studies the authors have shown that high-dose lysine alone is capable of causing acute renal failure. However, it has remained unclear what the morphologic expression of this type of acute renal failure is in the maintenance phase of the syndrome, whether other amino acids produce a similar lesion, and whether lysine in lower doses also produces acute renal failure. In the present study the authors show that lysine, when given in a dose of 600 mg/rat over 4 hours, produced persisting acute renal failure which at 48 hours was characterized morphologically by a picture similar to that in human "acute tubular necrosis"--little overt tubular necrosis, but a focal loss of individual tubular cells with regenerative changes and mitotic figures. Extensive hyaline cast formation was seen, particularly in the thin limbs of the loops of Henle, and these thin limb casts were shown to contain Tamm-Horsfall protein. Equivalent doses of glycine, arginine, and glutamic acid and lower doses of lysine produced no significant renal morphologic or functional changes.     

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.     

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.     

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.     

Renal papillary necrosis

Renal papillary necrosis (RPN) is a significant problem in human beings, especially in England and in Australia where it has been reported to account for 15% to 20% of patients needing renal transplants. Many compounds, including aspirin, phenacetin, phenylbutazone, indomethacin, mefenamic acid, flufenamic acid, fenoprofin, naproxen, and ibuprofen have been linked to renal papillary necrosis in human beings. Although the exact mechanism of RPN is unknown, there are several theories that have good scientific evidence behind them. Study of RPN in animals as models for the disease in human beings is limited by several factors, including anatomical differences between human beings and most animal species as well as technical difficulties in studying the renal papilla.     

2-Bromoethanamine nephrotoxicity in the nude mouse: an atypical targetting for the renal cortex

Male MF1-nu/nu/Ola/Hsd nude mice, maintained in a gnotobiotic environment, were dosed i.p. with either 50, 100 or 200 mg/kg 2-bromoethanamine (BEA) hydrobromide to induce a model papillary necrosis. Renal histological changes were examined in semithin glycolmethacrylate resin sections at 24, 48 and 72 h after BEA treatment. The sequence of medullary changes included pyknosis of interstitial cell nuclei, increased staining of the interstitial mucopolysaccharide matrix, platelets adhering to capillary endothelium, necrosis of collecting duct epithelial cells and denudation of the covering epithelium of the papilla. This was similar to that previously described in the Wistar rat, but the time course was extended. There was also a concomitant and extensive cortical necrosis of the P2 and P3 segments of the proximal tubule, which was evident prior to the onset of renal papillary necrosis at the higher doses of BEA. Nude mice show an atypical response to BEA compared to several mouse and rat strains, the hamster and pig, that suggests unique characteristics in this athymic murine mutant.     

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.     

The effect of vasopressin upon the vasculature of the isolated perfused rat kidney

The timed uptake of (131)I-labelled human serum albumin was used as an index of regional perfusion in the isolated rat kidney.1. Arginine vasopressin in doses of 1, 5 and 10 muu./ml. of perfusate decreased papillary perfusion. Total renal perfusion was decreased only by the 5 muu. dose.2. Ornithine-8-vasopressin in doses of 5 and 10 muu./ml. of perfusate decreased papillary perfusion. Total renal perfusion was decreased only by the 10 muu. dose.3. When the relative viscosity of the perfusate was increased to a value of 2.0 from the control value of 1.7, both papillary perfusion and total renal perfusion were reduced.4. Arginine vasopressin further reduced papillary flow in kidneys perfused with high viscosity artificial plasma.     

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.     

Nephrotoxic tubular and interstitial lesions: morphology and classification

Nephrotoxic renal injury, and especially drug nephrotoxicity is now a common cause of acute renal failure. The most common patterns of renal injury produced by nephrotoxins, tubular damage, and interstitial nephritis, are discussed here. Toxic agents which are primarily tubular toxins include certain antibiotics, cisplatinum, anesthetics, and radiocontrast agents. In tubules injured by toxins, alterations range from subtle ultrastructural abnormalities to extensive tubular necrosis. Mechanisms of tubular injury include direct tubular cell toxicity, and alterations in intrarenal blood flow producing secondary tubular damage. Other commonly used therapeutic agents, including the penicillins, other antibiotics, and non-steroidal anti-inflammatory agents, produce renal dysfunction by inducing interstitial nephritis. Long-term analgesic abuse is associated with a particularly striking interstitial damage with frank papillary necrosis. Criteria for differentiating primary tubular injury with inflammation and primary interstitial nephritis with tubular injury are discussed. Individual commonly-used therapeutic agents are considered in some detail, with discussion of both clinical and morphological aspects of drug nephrotoxicity.     

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.     

Experimental renal papillary necrosis. Effects of beta adrenergic receptor blockade, heparin and hydrocortisone.

Renal papillary necrosis was induced in rats by daily subcutaneous injection of 15 mg 2-bromoethylamine hydrobromide (BEA) per 100 g of body weight for 2 successive days. This dose was 50% higher than that reported previously. Beta adrenergic receptor blockade with oxyprenolol did not influence the kidney damage.The administration of heparin did not show any effect. The doses applied did not induce the incoagulability for a sufficient period of time. On the contrary, treatment with hydrocortisone decreased papillary necrosis without inducing increased diuresis.     

Analgesic-associated nephropathy

Summary Although the question of whether or not analgesic abuse leads to a certain type of nephropathy has been investigated since 1953, no conclusive answer has been forthcoming. Epidemiologic investigations on the correlation between analgesic abuse and renal function as well as experimental animal studies have given contradictory results concerning the possibility of analgesic-associated kidney damage. However, studies on the correlation between analgesic abuse and papillary necrosis have demonstrated that this lesion coincides in 69% of the cases with an analgesic history. Follow-up studies of patients with analgesic nephropathy have shown that renal function deteriorates in 60% of the patients with continued abuse and that it stabilizes in 80% of the patients after cessation of abuse. Studies on the legislative restriction of phenacetin/acetaminophen, carried out mostly in Scandinavian countries since 1965, show a 50%–90% decline in signs of analgesic nephropathy (papillary necrosis) following a reduction in the sale of these drugs. The prevalence of analgesic abuse may be underestimated, since up to 80% of the abusers tend to deny their analgesic intake. Obviously, only a small percentage of analgesic abusers (approximately 1%) finally develop nephropathy. Even though the results of epidemiologic and experimental studies are contradictory, the results of investigations on papillary necrosis and on legislative prevention as well as of patient follow-ups tend to indicate a correlation between analgesic abuse and a well-defined type of nephropathy.Abbreviations AAN analgesic-associated nephropathy - AA analgesic abuse - PN renal papillary necrosis     

RENAL PAPILLARY NECROSIS IN THE NEWBORN REPORT OF THREE CASES WITH AUTOPSY FINDINGS and REVIEW OF THE LITERATURE

Three cases of papillary necrosis in newborn infants are reported. In each instance the necrosis was associated with severe icterus with elevated concentrations of indirect-reacting bilirubin. Common clinical symptoms of these cases were, in addition to icterus, oliguria, anuria, and/ or hematuria. Rapid elevation of serum N.P.N, was observed.
Thirty-three reported cases of this rare condition have been reviewed, including twenty-four in the newborn.
Renal papillary necrosis may be caused by altered blood flow in the renal medulla. Deposition of high concentrations of bilirubin in the tubular epithelium of the renal medulla may act as a trigger of the lesion. ACTA PATH. JAP. 19: 419˜431, 1969.