Sulfur-containing amino acids that increase renal glutathione protect the kidney against papillary necrosis induced by 2-bromoethylamine

Papillary necrosis was observed in the kidneys of rats, 72 h after receiving a single injection of bromoethylamine (BEA). This effect was associated with renal glutathione (GSH) depletion 1 h after the administration of BEA. Stimulation of renal GSH synthesis by pretreatment of the animals either with glutamine + glycine + cystine or N-acetyl-L-cysteine was attempted. Low doses of these precursors administered previously to BEA, respectively, decreased or abolished the GSH depletion. Nevertheless, both pretreatments failed to modify the magnitude of renal papillary necrosis. High doses of these precursors did not modify the BEA-induced GSH depletion, but they significantly increased GSH levels 24 h after BEA administration. At this time, although a smaller intensity of renal papillary necrosis was observed with the amino acid mixture pretreatment, N-acetyl-L-cysteine pretreated rats showed no papillary necrosis. It is suggested that the observed protective effects against BEA-induced renal papillary injury may be ascribed in some measure, to a mechanism independent of GSH.     

Urographic Changes in Acute Papillary Necrosis in the Rat

Intravenous high-dosage urography was performed in rats which had renal papillary necrosis induced with ethyleneimine or renal tubular necrosis produced with mercuric chloride. In both groups, nephrograms were abnormally persistent. In animals treated with ethyleneimine dense selective opacification of the necrotic renal pyramid occurred. It is suggested that this selective opacification may be a valuable radiological sign of recent renal papillary necrosis.     

Effect of different amino acidic pretreatments that protect the kidney against papillary necrosis induced by bromoethylamine on differential distribution of renal nonprotein sulfhydryls

Content of nonprotein sulfhydryls (NPSH) was found to be higher in rat renal cortex than in external medulla and papilla. Administration of bromoethylamine (BEA), at a dose that produces extensive papillary necrosis and minor effects in the other renal segments, induced a significant reduction in NPSH levels of renal cortex and external medulla, with no changes in the papilla. Treatment with N-acetyl-L-cysteine (NAC) elicited an increase in papillary NPSH and a decrease in the cortex, with opposite changes being observed with an amino acid mixture of glutamine, glycine, and cystine (AM). Similar results were found in animals pretreated with NAC or AM prior to BEA intoxication. These pretreatments protect the cortex, external medulla, and papilla from the necrosis induced by BEA. It is suggested that protection of BEA-induced renal necrosis by NAC or AM pretreatments might be due to different mechanisms, with NPSH playing direct or indirect roles, respectively.     

I. Recognition of the problem of analgesic nephropathy

The incidence of renal impairment secondary to the abuse of analgesic compounds now accounts for a significant proportion of patients requiring renal replacement therapy. The clinical features of 100 cases of analgesic nephropathy are described; essentially these consist of otherwise unexplained renal impairment, urinary tract symptoms, radiological changes and sterile pyuria, often associated with dyspepsia, anemia and psychiatric disturbances. The classical pathological changes consist of interstitial nephritis and progressive reduction in renal size, secondary to repeated episodes of papillary necrosis. Cessation of analgesic abuse usually arrests the deterioration in renal function, and indeed some recovery of function may occur.     

Renal function studies in an experimental model of papillary necrosis in the rat

Twenty four hours after i.v. injection of bromoethylamine-hydrobromide (BEA) in rats, a uniform papillary necrosis is observed. The present study investigates the renal functional and the papillary haemodynamics in response to acute volume expansion (12% of body weight) in this model. Renal function studies were performed in hydropenic and volume expanded sham- or BEA-injected rats. In hydropenic normal animals a GFR of 1.97 +/- 0.14 ml/min, an urinary osmolarity (UOsm) of 1 011 +/- 94.5 mOsm/kg and a fractional sodium excretion (FENa) of 0.18 +/- 0.026% were obtained. In contrast, BEA-treated hydropenic animals showed a lower GFR (1.16 +/- 0.14 ml/min), UOsm (469 +/- 30.31 mOsm/kg) and a higher FENa (0.37 +/- 0.06%). In volume expansion a similar UOsm and FENa were obtained in both groups. The papillary plasma flow (PPF) was measured in each of the experimental groups by the albumin accumulation technique. The mean value in hydropenic normal animals was 50.65 +/- 2.12 m 100 g-1 min-1 and increased to 66.02 +/- 2.00 ml 100 g-1 min-1 after volume expansion (P less than 0.001). In BEA rats the PPF was 58.86 +/- 2.33 ml 100 g-1 min-1 in hydropenia (P less than 0.01 vs. control animals) and remained unchanged after volume expansion. Thus, during hydropenia, BEA-induced papillary necrosis results with a salt wasting state and an urinary concentration defect. After volume expansion no disturbance in sodium excretion capacity was observed. These results are compatible with the nephron-heterogeneity concept in the regulation of sodium excretion. The histological lesions cannot be explained by a decreased renal papillary plasma flow.     

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 Tubular Necrosis and Papillary Necrosis after Gastroenteritis in Infants

Three young infants who had severe gastroenteritis developed radiological and histological features of renal tubular necrosis. Characteristically the excretion urogram showed renal enlargement with prolonged and heavy opacification of the renal parenchyma and a pronounced increase in density of the pyramids. Subsequent radiological studies showed extensive papillary necrosis. Though these infants are now apparently fit, renal damage has occurred and this may eventually give rise to features indistinguishable from chronic pyelonephritis.     

Renal necrosis and the involvement of a single enzyme of the de novo pathway for the biosynthesis of platelet-activating factor in the rat kidney inner medulla

2-Bromoethylamine hydrobromide (BEA), when administered to rats, induces a highly specific papillary necrosis associated with the inner medulla. PAF levels in the blood were lowered by 50% and of the three enzymes that comprise the de novo route for PAF in the cortex/medulla, only the cholinephosphotransferase activity in the inner medulla microsomes was reduced (33%) by the BEA treatment. Moreover, BEA did not affect phosphatidylcholine synthesis in either the cortex or inner medulla. Our studies indicate that the de novo pathway for PAF synthesis in the renal inner medulla is responsible for the secretion of newly formed PAF into the blood stream and that a single enzyme in the de novo route accounts for the decreased rate of PAF synthesis during the development of renal necrosis.     

Retroperitoneal fibrosis in three siblings with the sickle cell trait

Three West-Indian black siblings with the sickle cell trait developed retroperitoneal fibrosis, a previously unreported association. Other well known renal manifestations associated with the sickle cell trait were also present in some of these cases and included renal medullary necrosis and spontaneous hematuria. It is postulated that the sickling of the erythrocytes in the periureteral vessels resulted in thrombosis, ischemia, reactive scarring and progressive fibrosis indistinguishable from the known histological picture of retroperitoneal fibrosis. The finding of fibrin thrombi in the small veins of the fibrotic tissue of one of these patients would support this explanation.     

Role of renal prostaglandins in the fall in urine osmolality after papillary micropuncture

The effect of micropuncture of the renal papilla through an intact ureter on urinary concentrating ability of rats was examined. Micropuncture of the renal papilla caused a fall in urine osmolality in the punctured kidney from 1718 +/- 106 to 1035 +/- 79 mosmol/kg X H2O. In order to investigate the role of renal prostaglandins in this process, PGE2 excretion was measured and found to increase from 63.4 +/- 14.0 to 205.5 +/- 57.1 pg/min. Urine osmolality and PGE2 excretion from the contralateral kidney were not significantly altered. In animals given meclofenamate (2 mg/kg X hr), renal PGE2 excretion was reduced to 22.3 +/- 5.1 pg/min prior to micropuncture and it remained low at 8.9 +/- 1.8 pg/min after papillary micropuncture. Meclofenamate also blocked the fall in urine osmolality caused by micropuncture of the renal papilla, with urine osmolality averaging 1940 +/- 122 before and 1782 +/- 96 mosmol/kg X H2O after the micropuncture. These results indicated that papillary micropuncture through an intact ureter increased renal PGE2 excretion and that a rise in renal production of PGE2 or some other prostanoid is associated with a fall in urine concentrating ability.     

Effect of 16,16-dimethyl PGE2 on renal papillary necrosis and gastrointestinal ulcerations (gastric, duodenal, intestinal) produced in rats by mefenamic acid

Mefenamic acid, given orally to rats at a single dose of 1200 mg/kg, produced renal papillary necrosis (RPN) in 63% of animals. The incidence was reduced to 27% by 16,16-dimethyl PGE2 (dmPGE2), given at an oral dose of 0.75 mg/kg t.i.d. RPN is likely to be caused by the renal prostaglandin depletion elicited by mefenamic acid, an inhibitor of prostaglandin cyclooxygenase. Substitution with dmPGE2 reduces RPN presumably by preventing the prostaglandin depletion. We conclude that the prostaglandin used is cytoprotective for the kidney. Mefenamic acid, like most nonsteroidal anti-inflammatory compounds (NOSAC), produced ulcerations of the small intestine (jejunum and ileum). These were prevented by dmPGE2 (intestinal cytoprotection). Unlike most other NOSAC, however, mefenamic acid produced duodenal ulcers in nearly all animals (80%). Of these ulcers, 88% were perforated. Twenty-five of the twenty-six animals that died had a perforated ulcer. These duodenal ulcers were also prevented by dmPGE2. Mefenamic acid-induced ulcers could be used as an experimental model for testing agents with a potential for preventing or healing duodenal ulcers.     

Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up.

OBJECTIVE--Determination of the long term incidence of uraemia, hypertension, and toxaemia in pregnancy associated with non-obstructive focal renal scarring after pyelonephritis in childhood 25-35 years earlier. DESIGN--27 Year follow up of patients with non-obstructive focal scarring identified from a retrospective review of intravenous urograms performed in childhood between 1951 and 1967. SETTING--Paediatric primary referral centre and urological clinic in tertiary referral centre. PATIENTS--30 Patients (mean age 33 (range 22-41] with non-obstructive focal renal scarring first detected between 1951 and 1967 and a history of febrile urinary tract infection. MAIN OUTCOME MEASURE--Hypertension and complications of renal damage. RESULTS--Three patients had developed end stage renal disease, seven had developed hypertension, two of 16 women had a history of toxaemia during pregnancy, and seven patients had undergone renal surgery during follow up. Of the 20 patients who had neither had renal surgery nor had end stage renal disease, all had a significantly lower glomerular filtration rate and renal plasma flow and higher diastolic blood pressure, mean arterial blood pressure, plasma renin activity, and serum beta 2 microglobulin concentration than 13 healthy age matched controls. Diastolic blood pressure and plasma renin activity were positively correlated (r = 0.50, p less than 0.05) and so were fractional sodium excretion and both systolic and diastolic blood pressures (r = 0.54, p less than 0.01, r = 0.51, p less than 0.01 respectively). The progress of renal damage was unrelated to the incidence of recurrent infections. CONCLUSIONS--Children with focal renal scarring due to pyelonephritis are at high risk of serious long term consequences. It is essential that they are given adequate attention and care during adolescence and pregnancy.     

N-Acetyl-l-cysteine abolishes the bromoethylamine-induced choline incorporation into renal papillary tissue

The role of regenerative processes in the protective effect of N-acetyl-L-cysteine (NAC) against bromoethylamine-induced renal papillary necrosis was assessed in rats given bromoethylamine (BEA) (1.2 mmol/kg), N-acetylcysteine (6 mmol/kg), or N-acetylcysteine plus BEA. Renal papillary slices were dissected after 15 hours of treatment, and ¹⁴C-choline incorporation into total phospholipid, lysophosphatidylcholine, sphingomyelin, and phosphatidylcholine was measured. Bromoethylamine elicited an increase in the incorporation of ¹⁴C-choline into choline-containing phospholipid, an effect that was abolished when N-acetylcysteine was administered prior to bromoethylamine. These studies indicate that the defensive mechanism of N-acetylcysteine against bromoethylamine-induced renal papillary necrosis is not related to regenerative processes and that N-acetylcysteine abolishes the bromoethylamine-induced choline incorporation into papillary phospholipid. © 1996 John Wiley & Sons, Inc.     

Cytologic and histologic findings in multiple renal hybrid oncocytic tumors in a patient with Birt-Hogg-Dubé syndrome: a case report

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant neoplastic syndrome characterized by multiple skin lesions, lung cysts and renal tumors. A variety of histologic types of renal tumors have been reported, including clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, oncocytoma and a recently described hybrid oncocytic tumor, which is thought to be highly associated with BHD. CASE: We report a case of a 48-year-old woman with BHD who initially presented to our institution with spontaneous pneumothorax and was found to have multiple lung cysts and renal tumors on computed tomography. We describe the fine needle aspiration findings of one of the renal tumors, which was suggestive of so-called hybrid oncocytic tumor. We also describe the gross and histologic findings of the multiple kidney tumors that the patient subsequently had excised. CONCLUSION: When multiple kidney tumors from a single patient appear oncycytic on fine needle aspiration, especially when focal clear cells are present, the possibility of oncocytomas and hybrid tumors associated with BHD must be entertained.     

Changes in cAMP reception in the cytosol of the developing rat kidney

The age-dependent changes in the cAMP-binding activity of renal papillary cytosol were studied in intact rats and in animals with experimental delay in development of the concentrating renal function induced by hydrocortisone injection in early postnatal period. The age dynamics of specific cAMP binding in the experimental group differ significantly from that in intact and control (sham injected) animals. It is suggested that the developmental changes in experimental animal kidneys are due to disturbances in hormonal regulation of renal tissue differentiation caused by the changes in intracellular receptors of cAMP. Another possible reason for the observed delay of development of the renal function is the weakening of the stimulating effect of endogenous cAMP on the genome function due to cAMP receptor deficiency in the cell.     

Polioencephalomalacia-like disease in pronghorns (Antilocapra americana)

A disease resembling thiamine-responsive polioencephalomalacia of domestic ruminants is described in four wild pronghorn from Saskatchewan. One animal was found dead, two were recumbent and unable to rise and the fourth was staggering and ataxic. Lesions were confined to the brain and consisted of brain swelling with herniation, symmetrical hemorrhagic foci in the thalamus and brainstem, and laminar necrosis of cortical neurons. All animals had been eating grain prior to their death. Possible pathogenetic mechanisms including changes in rumen microflora resulting in thiamine deficiency, plant and salt intoxication are discussed.     

Review of papillary renal cell carcinoma with focus on clinical and pathobiological aspects

Recent studies have shown that papillary renal cell carcinoma (RCC) is clinically and genotypically a distinct entity. Papillary RCCs account for about 10-15% of renal parenchymal neoplasms. Macroscopically, the cut surface is yellow or brown in color and large tumors frequently show cystic change. Hemorrhage and necrosis are common. Histologically, Delahunt and Eble have classified papillary RCCs into type 1 (small cells, single layer) and type 2 (large cells, pseudostratification) according to the cytoplasmic volume and thickness of the lining cells. In chromosomal analysis, gain of chromosomes 7 and 17, loss of Y chromosome and additional gains (chromosome 3q, 8p, 12q, 16q and 20q) are frequently found in type 1 papillary RCCs, but the chromosomal aberration of type 2 papillary RCCs seems to be more heterogenous than that of type 1 papillary RCCs. Mutations of MET proto-oncogenes in some cases of both hereditary and sporadic papillary RCCs have recently been detected. Furthermore, all hereditary and sporadic papillary RCCs with MET proto-oncogene show type 1 histological features. Type 1 papillary RCCs generally seem to have a favorable prognosis, but type 2 tumors have a worse prognosis than do type 1 tumors. Papillary RCCs with involvement of the X chromosome and cancer syndrome with predisposition to cutaneous/uterine leiomyomas and papillary RCCs, the histological features of which are basically different from those of usual papillary RCCs, have also been recently reported. Since papillary RCCs seem to constitute clinically, histologically, and even genetically more heterogenous groups than previously thought, further investigations are needed to characterize the subtype of papillary RCC.     

Characterization of biological properties of synthetic and biological leukotriene B3

The effect of micropuncture of the renal papilla through an intact ureter on urinary concetrating ability of rats was examined. Micropuncture of the renal papilla caused a fall in urine osmolality in the punctured kidney from 1718 ± 106 to 1035 ± 79 mosmol/kg·H₂O. In order to investigate the role of renal prostaglandins in this process, PGE₂ excretion was measured and found to increase from 63.4 ± 14.0 to 205.5 ± 57.1 pg/min. Urine osmolality and PGE₂ excretion from the contralateral kidney were not significantly altered. In animals given meclofenamate (2 mg/kg·hr), renal PGE₂ excretion was reduced to 22.3 ± 5.1 pg/min prior to micropuncture and it remained low at 8.9 ± 1.8pg/min after papillary micropuncture. Meclofenamate also blocked the fall in urine osmolality caused by micropuncture of the renal papilla, with urine osmolality averaging 1940 ± 122 before and 1782 ± 96 mosmol/kg·H₂O after the micropuncture. These results indicated that papillary micropuncture through an intact ureter increased renal PGE₂ excretion and that a rise in renal production of PGE₂ or some other prostanoid is associated with a fall in urine concentrating ability.     

Pregnancies in women with and without renal scarring after urinary infections in childhood.

OBJECTIVE--To compare the outcome of pregnancy in women with and without renal scarring after childhood urinary infections with that in unmatched controls. DESIGN--Retrospective study of pregnancies in women prospectively followed up from their first recognised urinary infection. SETTING--Tertiary referral centre in Gothenburg. SUBJECTS--111 Women attending an outpatient clinic for women with urinary infection during 1975-83, of whom 41 (65 pregnancies) were studied (19 women with renal scarring (32), 22 without scarring (33)), and 65 controls (65) randomly selected and matched for parity, age, smoking habits, and date of delivery. MAIN OUTCOME MEASURES--Urinary infections and complications in pregnancy. RESULTS--The incidence of bacteriuria during first pregnancies was significantly greater in women with (9, 47%) and without (6, 27%) renal scarring after childhood urinary infection than in controls (1, 2%) (p less than 0.001, 0.01 respectively). Symptomatic infections were seen only among women with a history of urinary infection: four women with renal scarring (three of whom had vesicoureteric reflux) developed pyelonephritis and three cystitis, and one woman without scarring developed pyelonephritis. Mean blood pressure was higher among women with severe renal scarring than controls (4/11 v 3/44; p less than 0.05) before and during pregnancy. There was no significant difference in the incidence of pre-eclampsia, operative delivery, prematurity, or birth weight. CONCLUSIONS--Women with a history of previous urinary infections had a high incidence of bacteriuria during pregnancy, and those with renal scarring and persistent reflux were prone to develop acute pyelonephritis. The risk of serious complications in pregnancy, however, was not increased in women with severe renal scarring, possibly owing to their continuous clinical supervision.     

Analgesic Nephropathy: Clinical Syndrome and Prognosis

Over a five-year period 86 patients presented to a renal unit with a history of prolonged analgesic abuse and no other obvious cause of renal damage. Anaemia and peptic ulceration were common, and neurological states suggestive of chronic analgesic intoxication occurred in 22 patients. Thirty-two patients died during follow-up, but the prognosis was much better in patients who ceased abuse of compound analgesics, and improvement could occur even in advanced renal failure. While 84 patients had taken mixtures containing both aspirin and phenacetin, papillary necrosis was also found in two patients who had abused only aspirin, and when phenacetin was withdrawn from several leading compound analgesics, renal function continued to deteriorate in patients ingesting those preparations.