Enhancement by potent diuretics of renal tubular necrosis induced by cephaloridine

1. Administration of frusemide or ethacrynic acid to cephaloridine-treated mice increased both the incidence and extent of proximal renal tubular necrosis compared with that obtained in cephaloridine-treated control mice.2. Administration of frusemide to cephaloridine-treated rats produced significant changes in urine output, electrolyte excretion and proteinuria, and plasma urea nitrogen and creatinine values were significantly increased compared with controls or rats that received frusemide or cephaloridine alone.3. Histological examination of the kidneys showed a higher incidence and greater extent of tubular necrosis in rats that received both frusemide and cephaloridine.4. It is suggested that this adverse drug interaction may have contributed to the deterioration in renal function observed in some patients treated with diuretics and cephaloridine concurrently.     

Polymeric micellar delivery reduces kidney distribution and nephrotoxic effects of Cyclosporine A after multiple dosing

The aim of this study was to test the ability of poly(ethylene oxide)-b-poly (epsilon-caprolactone) (PEO-b-PCL) micelles to reduce the renal uptake and nephrotoxicity of Cyclosporine A (CyA) after multiple dose administration. Sprague-Dawley rats received CyA i.v. at a dose of 20 mg/kg/day delivered as the commercial formulation (Sandimmune) or polymeric micellar formulation (PM-CyA). Cremophor EL (the solubilizing agent in Sandimmune), unloaded PEO-b-PCL micelles, or normal saline were also administered i.v. to control rats. After 7 days, kidney function was assessed through measurement of creatinine (CLcr) and urea clearances, as well as electrolyte concentrations in plasma. Blood and kidney were collected and assayed for CyA. Sandimmune administration led to decreased CLcr, and increased urea and potassium levels in plasma. In contrast, functional nephrotoxicity with the PM-CyA was not apparent, as the CLcr did not change significantly. The rate of increase in body weight in control rats was 3.1-3.4% per day. Weight gains (1.8% per day) were also noted in the rats given PM-CyA, although the body weight of animals receiving Sandimmune remained constant. Compared to Sandimmune, polymeric micelles reduced kidney uptake of CyA by 2.6-fold, and increased CyA levels in blood by 2.1-fold. The results show a potential for PEO-b-PCL micelles in restricting the nephrotoxicity of CyA.     

The safety of cefuroxime and gentamicin in patients with reduced renal function

Summary

The glomerular and tubular function of 7 patients with a spectrum of renal impairment was measured before, during and after 4-days' treatment with cefuroxime and gentamicin. Neither the mean plasma urea nor creatinine concentrations of the group increased after combined treatment, nor was the excretion of cefuroxime slowed. The ability to acidify and to concentrate the urine did not change. In only 1 patient did plasma creatinine increase and GFR fall. This patient had an unexpectedly high plasma gentamicin concentration and was taking frusemide. However, an eighth patient with acute renal failure caused by bacteraemic shock rapidly recovered renal function while being treated with cefuroxime and gentamicin for 15 days after large doses of frusemide intravenously. This limited study suggests that the useful combination of cefuroxime and gentamicin need not be denied to patients with reduced renal function, but emphasizes that the plasma gentamicin concentration must always be monitored.     

Frusemide pretreatment blunts the inhibition of renal tubular sodium reabsorption by ANF in man

Summary The effects of atrial natriuretic factor (ANF) 15 pmol/kg/min on renal function were studied in 7 normal male volunteers during maximal water diuresis. Subjects were studied in neutral salt balance either before, or after, seven days treatment with 40 mg oral frusemide. The post-frusemide state was associated with activation of the renin-angiotensin system (RAAS) and generally higher noradrenaline levels; this state was also associated with sodium retention, mainly due to enhanced distal nephron reabsorption.Without diuretic pretreatment ANF produced a natriuresis and diuresis associated with inhibition of both proximal and distal nephron sodium reabsorption. In contrast, after frusemide pretreatment, ANF caused an increase in water excretion (urinary flow rate) but no change in sodium excretion. In the post-diuretic condition ANF did not affect renal tubular handling of sodium.The enhanced tubular reabsorption of sodium post-frusemide, and the failure of ANF to suppress this, could be due to activation of the RAAS and SNS.     

Effectiveness of ibopamine in the management of ascitic liver cirrhosis--a controlled study v placebo and frusemide.

1 Thirty in-patients of both sexes suffering from ascitic liver cirrhosis were divided into three groups treated with (a) a placebo, (b) ibopamine (SB 7505, a new oral dopaminergic drug) and (c) frusemide, for 10 days. 2 Body weight decreased with both frusemide and ibopamine, diuresis and urinary excretion of Na+ and Cl- increased with both drugs; whereas urinary excretion of K+ increased only with frusemide. 3 An important difference between the frusemide and ibopamine treatment was encountered in creatinine clearance, which increased only with ibopamine, and in blood uric acid which increased only with frusemide. 4 The antidiuretic hormone (ADH) in the plasma of cirrhotic patients was lower than the sensitivity limit of the radioimmunoassay method, whereas in a group of healthy subjects it could be clearly measured. 5 The treatments did not affect systolic or diastolic blood pressure, heart rate, or a series of haematochemical parameters. 6 The increase in diuresis and creatinine clearance and the very good tolerability encountered with ibopamine highlight this new oral dopamine agonist as a useful drug in the management of liver cirrhosis.     

Oral piretanide in chronic renal failure.

1 The effects of high doses of piretanide, a new diuretic agent chemically related to frusemide and bumetanide were evaluated in twelve patients with severe chronic renal insufficiency (creatinine clearance below 25 ml/min). 2 Patients received either 30 mg or 60 mg piretanide orally after a water load of 11. Urine volume and the excretion of electrolytes, creatinine, urea and uric acid were measured over the subsequent 24 h. 3 Piretanide produced an effective diuresis and natriuresis in these patients, its action being broadly similar to those of bumetanide and frusemide observed in previous studies.     

Effects of STZ-induced diabetes and its treatment with vanadyl sulphate on cyclosporine A-induced nephrotoxicity in rats

The aim of this study was to analyze the effect of streptozotocin (STZ)-induced diabetic state and the insulin-like acting, vanadyl sulphate (VS) on cyclosporine A (CyA) related nephrotoxicity in rats. Male Wistar rats were divided into six groups, of 12 animals each: The control, diabetic rats and diabetic rats whose drinking VS in the drinking water in a concentration of 1 mg/ml. Another three similarly treated groups were injected intra-peritoneally (ip) with CyA in a dose of 25 mg/kg/day for ten doses, 10 days after diabetic induction by using a single dose of STZ of 65 mg/kg. Rats were sacrificed 48 h after the last CyA dose and serum as well as kidneys were isolated and analyzed. Treatment with CyA to control normoglycemic rats resulted in significant increases in kidney weight, serum creatinine, urea nitrogen, cholesterol and triglycerides (TG) levels. Also, the kidney tissue of CyA-treated control animals showed significant increases in total nitrate/nitrite (NO_x) concentration and malondialdehyde (MDA) production level as well as depletion of glutathione (GSH) content and glutathione peroxidase (GSH-P_x) activity level. Histopathologic evaluation of CyA-treated control rats revealed tubular atrophy, hyaline casts and focal tubular necrosis. However, treatment of diabetic rats with CyA showed significant reduction in serum creatinine and elevation in TG level as well as reductions in the kidney NO_x concentration and MDA production level and increase in GSH concentration compared to CyA-treated control rats. Moreover, histopathology of the kidney of CyA-treated diabetics showed typical changes of the diabetic controls revealing glomerular hypertrophy and tubular dilation. On the other hand, treatment with CyA to those diabetic animals administered VS in the drinking water resulted in exacerbation of renal dysfunction, manifested by significant increases in serum indices of nephrotoxicity, cholesterol, TG and bilirubin levels. Also, VS administration to CyA-treated diabetics showed significant increase in kidney NO_x concentration compared to those CyA-treated diabetics drinking plain tap water, and to a level significantly lower than those CyA-treated controls. Histopathologically, kidney of CyA/VS-treated diabetic showed marked CyA related changes. In conclusion, STZ-induced diabetes might provide partial protection against CyA-induced renal dysfunction. Also, treatment of hyperglycemia with VS might exacerbate CyA related nephrotoxicity.     

Urinalysis for detection of chemically induced renal damage (1)--Changes in urinary excretions of enzymes and various components caused by mercuric chloride and gentamicin

In order to establish sensitive methods of detecting minor renal damage, changes of enzymes, tubular cell counts, and creatinine in the urine were investigated in rats that had been given nephrotoxic chemicals. Daily administration of mercuric chloride (HgCl2) dose-dependently increased urinary excretions of lactate dehydrogenase (LDH), aspartate aminotransferase (GOT), alkaline phosphatase (ALP), leucine aminopeptidase (LAP), lysozyme (LZM), N-acetyl-beta-D-glucosaminidase (NAG), and acid protease together with increased counts of tubular cells in the urine. The increase in tubular cell counts and the change in urinary LDH isoenzyme profile preceded the changes in the other enzymes. Daily administration of gentamicin (GM) increased urinary excretions of LDH, GOT, LZM, NAG, acid protease and tubular cell counts in a dose-dependent manner, but did not increase gamma-glutamyl transpeptidase (gamma-GTP) and ALP excretions. The urinary isoenzyme profiles of LDH in rats treated with GM were different from those with HgCl2. The increase in acid protease excretion outlasted those in LDH and GOT in the high dose group. It was concluded that the severity of renal damage can be readily detected by periodic determinations of the following urinary parameters: tubular cell counts, LDH isoenzyme, acid protease, LZM and NAG, in addition to either LDH or GOT and one of the enzymes ALP, LAP or gamma-GTP. Furthermore, the site of renal damage can be presumed from these results.     

Effects of cyclosporin A, gentamicin and furosemide on rat renal function: a lithium clearance study

1. This study applied clearance methods of inulin, lithium, potassium, sodium and para-aminohippuric acid (PAH) for investigation of the effects of cyclosporin A (CyA), furosemide and gentamicin on rat (n = 92) renal function. The drugs were dosed for 2 weeks; CyA 12.5 mg/kg per day, gentamicin 32 mg/kg per day and furosemide 5 mg/kg per day. 2. The questions asked were: could these methods differentiate the effects of drugs with different sites of action, and would gentamicin or furosemide exaggerate the nephrotoxicity of CyA? 3. Furosemide increased sodium clearance (CNa) 74% and fractional sodium clearance (FENa) 105%, while fractional sodium reabsorption in the distal nephron (FDNR) was reduced, compared with placebo-treated controls. 4. Gentamicin reduced CPAH 29% and Cin 37%, while FENa increased 335%. Proximal fractional reabsorption (PFR) and absolute proximal reabsorption (APR) decreased. 5. CyA depressed CPAH 32% and lithium clearance (CLi) 56%, and increased PFR. 6. The effects of CyA and furosemide in reducing renal function were not additive. 7. CyA plus gentamicin reduced CPAH to 35% of the value in untreated controls, equal to 52% of the CPAH of CyA-treated rats; Cin was reduced to 46% of the Cin of CyA-treated rats. 8. Rats given CyA, furosemide and gentamicin had decreased Cin, CPAH and CLi compared with rats given either CyA plus furosemide or gentamicin plus furosemide. 9. Thus, in this investigation of drugs known to have different sites of actions, the differences in renal and tubular function were discernible with the lithium clearance method. 10. The nephrotoxicities of CyA and of gentamicin were additive, while furosemide did not aggravate CyA nephrotoxicity.     

阿魏酸钠对UUO大鼠肾脏保护作用的实验研究

目的探讨阿魏酸钠对UUO大鼠肾脏保护作用及其可能的机制。方法将SD大鼠随机分为假手术组、UUO模型组、阿魏酸钠治疗组,每组20只。术后14 d处死动物并取梗阻侧肾脏,比较病理改变;采用免疫组化法检测3组大鼠肾小管上皮细胞TGF-β1、p-p38、α-SMA的表达。处死大鼠同时心脏取血,检测3组血清肌酐、尿素氮及光抑素C水平。结果与假手术组比较,模型组TGF-β1、p-p38、α-SMA的表达显著升高(P<0.05)。与模型组比较,治疗组血清肌酐、尿素氮及光抑素C水平明显降低(P<0.05);而肾小管上皮细胞TGF-β1、p-p38、α-SMA的表达显著降低(P<0.05)。结论阿魏酸钠可能通过下调肾小管上皮细胞TGF-β1、p-p38及α-SMA的表达,起到延缓肾间质纤维化进程及保护肾功能的作用。     

Inhibitory effect of captopril on renal responses to frusemide in sodium-restricted rats

Indomethacin (10 mg kg-1 orally) caused a moderate inhibition of the renal responses to frusemide (30 mg kg-1 orally) only in Na+-deficient rats, suggesting that renal prostaglandins (PG) are necessary for optimal effects of frusemide during Na+ restriction. Captopril (1, 3 and 10 mg kg-1 orally) also inhibited frusemide-induced diuresis and natriuresis in Na+-deficient rats; the large effect of captopril at 10 mg kg-1 was accompanied by arterial hypotension. In normal rats, captopril did not disturb blood pressure or affect the renal effects of frusemide. By comparison, minoxidil (10 and 20 mg kg-1 orally) caused hypotension and reduced the natriuretic effects of frusemide in both normal and low-Na+ states. Since circulating angiotensin II (AII) is a stimulus for PG synthesis during Na+ restriction, it is suggested that captopril may impair the renal responses to frusemide through hormonal and haemodynamic changes resulting from inhibition of A II formation.     

Diltiazem enhances gentamicin nephrotoxicity in rats

The effect of the calcium antagonist, diltiazem, was examined in gentamicin-induced nephrotoxicity states in rats. Animals were injected for 5 days with diltiazem intraperitoneally (40 mg/kg/day), or gentamicin subcutaneously (100 mg/kg/day) or simultaneously with both preparations using the same doses. At the time of sacrifice, the urea and creatinine clearances, as well as urine osmolality were determined and the renal tissues were processed for examination by light microscopy. Gentamicin-injected rats demonstrated the typical pattern of aminoglycoside nephrotoxicity characterized by poliuric renal failure and necrosis of the proximal tubular epithelium. Rats injected with diltiazem revealed only mild depression of urine osmolality. There was no elevation of blood urea nitrogen and serum creatinine or depression of urea and creatinine clearances, and no focal tubular cell necrosis was detected. However, concomitant administration of both compounds considerably increased nephrotoxicity by according both histological indications and renal function measurements. Thus, we conclude that the combination of diltiazem and gentamicin must be used carefully in human clinical practice.     

硝酸铋预处理对顺铂肾毒性的防护作用

大鼠预先sc硝酸铋(30μmol·kg~(-1)·d~(-1))连续3d,可显著降低肾毒性剂量顺铂(5mg·kg~(-1))引起的尿蛋白含量,尿NAG活性和BUN水平的升高;并可有效地防护顺铂造成的肾脏髓层外带近端小管坏死,铋对肾脏MT合成有诱导作用,这可能与其防护顺铂的急性肾毒性有关。     

Effects of low-level arsenic exposure on urinary N-acetyl-β-D-glucosaminidase activity

This study was aimed to evaluate whether renal tubular function is impaired by exposure to relatively low concentrations of arsenic. Mean urinary arsenic concentrations and N-acetyl-β-D-glucosaminidase (NAG) activities were compared among 365 and 502 Korean men and women, respectively, in relation to gender, smoking, alcohol consumption, and recent seafood consumption. The study subjects were divided into 4 groups according to urinary NAG activity and seafood consumption prior to urine sampling, and the correlation between arsenic concentration and urinary NAG activity was tested for each group. The mean urinary arsenic level was higher in women, non-smokers, and non-drinkers in comparison to men, smokers, and drinkers, respectively. Individuals who consumed seafood within 3 days prior to urine sampling showed a higher mean urinary arsenic level than those who did not. The correlation between urinary arsenic concentration and NAG activity in urine was significant only in subjects who did not consume seafood within 3 days prior to urine sampling and whose urinary NAG activity was 7.44 U/g creatinine (75th percentile) or higher. The urinary arsenic concentration was a significant determinant of urinary NAG activity in subjects with NAG activity higher than 7.44 U/g creatinine and especially in those who had not consumed seafood recently. These facts suggest that a relatively low-level exposure to inorganic arsenic produces renal tubular damage in humans.     

Prostaglandins and aminoglycoside nephrotoxicity

The role of prostaglandins in the development of aminoglycoside-induced acute renal failure was studied in CD-COBS rats (200 to 250 g). The animals were treated with gentamicin (80 mg/kg), acetylsalicylic acid (ASA, 100 or 200 mg/kg), or both drugs or saline for 5 or 10 days. Renal function was studied measuring creatinine clearance, blood urea nitrogen (BUN), and serum electrolytes, urine osmolality, and maximal urinary concentrating capacity after water deprivation and vasopressin administration. Gentamicin toxicity on the proximal tubule was evaluated by measuring urinary excretion of the lysosomal enzyme N-acetylglucosaminidase (NAG). Renal prostaglandin (PG) production was evaluated measuring the concentration of PGE2, PGD2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) in whole renal homogenate after a 15-min incubation at 37 degrees C using gas chromatography-mass spectrometry. Gentamicin alone reduced the glomerular filtration rate (GFR) 20 to 30% after 5 and 10 days of treatment. Combination with ASA potentiated the toxic effect of the aminoglycoside after 10 but not after 5 days of treatment. Similarly, gentamicin reduced the urinary concentrating capacity and addition of ASA worsened the effects. Gentamicin markedly increased NAG excretion but this effect was reduced by ASA, probably as a result of lysosomal stabilization. ASA alone inhibited the production of prostaglandins in renal tissue by 70 to 90% after single or multiple doses. The animals treated with gentamicin alone presented a significant, specific increase in PGE2 production after 10 days of treatment but this increase did not occur when the two compounds were given together. Since PGE2 has a vasodilatory effect in the kidney these results suggest that it may play a specific role in maintaining normal renal blood flow and GFR during the development of aminoglycoside nephrotoxicity. The inhibition of prostaglandin production by nonsteroid anti-inflammatory drugs prevents this compensatory mechanism and worsens the renal damage.     

Urinalysis for detection of chemically induced renal damage (2)--Changes in urinary excretions of enzymes and various components caused by p-aminophenol, puromycin aminonucleoside and hexadimethrine

In order to establish sensitive methods of detecting minor renal damage, changes of enzymes, protein, tubular cell counts, and creatinine in the urine were investigated in rats to which nephrotoxic chemicals had been administered. Daily administration of p-aminophenol (PAP) dose-dependently increased urinary excretions of lactate dehydrogenase (LDH) and its isoenzymes (LDH5 = LDH4 greater than LDH3 greater than LDH2 = LDH1), aspartate aminotransferase (GOT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (gamma-GTP), leucine aminopeptidase (LAP), lysozyme (LZM), N-acetyl-beta-D-glucosaminidase (NAG) and acid protease together with increased counts of tubular cells in the urine. Tubular cell counts, LDH and GOT were more sensitive indicators in the PAP tubulonephritis. Single i.v. injection of puromycin aminonucleoside (PM) dose-dependently increased urinary excretions of LDH and its isoenzymes (LDH1 = LDH5 greater than LDH2 = LDH4 greater than LDH3), GOT, NAG, acid protease and protein but degree of the increases in these enzymes was lower than those in the rats treated with PAP. PM increased excretions of high molecular weight proteins but did not increase ALP, gamma-GTP, LAP, LZM and tubular cells excretions. Single i.v. injection of hexadimethrine increased urinary excretion of LDH and its isoenzymes (LDH1 = LDH5 greater than LDH2 greater than LDH3 = LDH4), GOT, LZM, NAG and acid protease together with increased counts of tubular cells in the urine but did not increase ALP, gamma-GTP and LAP excretions. It is concluded that tubular cell counts, LDH isoenzymes and battery of these enzymes in urine are useful markers for detecting the severity and the site of renal damage in addition that urinary protein is a useful marker for detecting glomerular damage.     

抗肿瘤抗生素博安霉素对大鼠肾功能及形态学的影响

研究了抗肿瘤抗生素博安霉素（boanmycin）对大鼠肾功能及病理形态学的影响。在急性和亚急性毒性实验中，博安霉素引起大鼠血清尿素氮、血清肌酐、尿蛋白等明显增加，且具有剂量依赖性。大鼠毒性反应后期，肾皮质区细胞广泛变性坏死；超微结构显示近曲小管上皮细胞微绒毛肿胀，线粒体肿大，排列紊乱，细胞核固缩或核溶解。     

Usefulness of the assessment of urinary enzyme leakage in monitoring acute fluoride nephrotoxicity

A single oral dose of sodium fluoride (NaF) in aqueous solution was given to male Wistar rats. Twenty-four-hour urine samples were collected and examined to evaluate fluoride-induced acute renal damage. The following parameters were measured in 24-h urine: urine volume and urinary excretion of fluoride, N-acetyl-β-d-glucosaminidase (NAG), α-glutathione-S-transferase (α-GST), and creatinine (CR). Fluoride exposure produced specific, dose-dependent changes of these parameters. Significant increases of fluoride and fluoride-induced polyuria were observed. NAG as specific marker of proximal convoluted tubule (PCT) function showed a significant increase when the lowest dose of fluoride was administered. At this minimal dose, α-GST, a specific marker for the S3 segment, did not show a significant increase but presented the strongest relationship (r = 0.83) to fluoride dose. No significant changes were measured for CR excretion, which showed a low correlation coefficient (r = 0.36) to administered fluoride. The specific differences in the increase pattern of these parameters show that the PCT is more susceptible to damage by low-dose fluoride than the S3 segment or the glomerulus. We concluded that both NAG and α-GST are useful for the diagnosis of fluoride-induced acute nephrotoxicity. Proper evaluation of these urinary indices may be of help to establish the site and extent of kidney injury in acute fluoride toxicity. Received: 9 February 1999 / Accepted: 19 April 1999     

The acute toxic effects of paraquat and diquat on the rat kidney.

The bipyridyls, paraquat and diquat, cause mild renal tubular damage in the rat. A marked diuresis, albuminuria, glucosuria, and an increased plasma urea concentration occurred 6–24 hr after paraquat (680, po, or 108 μmol/kg, sc) and an increased urinary excretion of N-acetyl-β-d-glucosaminidase occurred 6–24 hr after paraquat (680 μmol/kg, po). Diquat (680 μmol/kg, po) produced proteinuria and glucosuria 6–24 hr after dosing. Histological examination of the kidneys showed there was mild hydropic degeneration of the proximal convoluted tubules. Mercuric chloride (HgCl₂), a nephrotoxic agent, was used as a positive control in these studies dosed at 7.4 μmol/kg, sc, and produced marked tubular necrosis. Biochemical studies showed that both paraquat and diquat decrease N′-methylnicotinamide (NMN) but not p-aminohippurate (PAH) accumulation by renal cortical slices when added in vitro, suggesting competition for the base transport system. However, no decrease in NMN or PAH accumulation was seen in renal cortical slices from rats treated with paraquat or diquat. Both bipyridyls stimulated pentose phosphate pathway and inhibited fatty acid synthesis when added in vitro to renal cortical slices. However, neither of these parameters were affected in renal cortical slices prepared from rats treated with paraquat or diquat. We conclude that both bipyridyls cause renal tubular damage but this damage is mild compared with that seen after HgCl₂. And that biochemical indicators of paraquat damage in the lung are not altered in renal cortical slices from bipyridyl-treated rats. These minimal changes observed using histological and biochemical techniques contrast sharply with the effects these compounds have on renal excretory function.     

N-(3,5-Dichlorophenyl)succinimide nephrotoxicity in the Fischer-344 rat

The nephrotoxic potential of N-(3,5-dichlorophenyl)succinimide (NDPS) was examined, in male Fischer-344 rats. Rats were administered NDPS (0.1, 0.2, 0.4 or 1.0 mmol/kg intraperitoneally (i.p.) or sesame oil (2.5 ml/kg, i.p.), and renal function was monitored at 24 and 48 h. NDPS (0.1 mmol/kg) stimulated organic ion uptake at 48 h. NDPS (0.2 mmol/kg) produced diuresis but did not alter blood urea nitrogen (BUN), kidney weight or organic ion uptake by renal cortical slices at 48 h. High-dose NDPS (0.4 and 1.0 mmol/kg) administration produced diuresis, decreased accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA), increased BUN and kidney weight and caused acute tubular necrosis. At 24 h, NDPS (0.2 mmol/kg) decreased uptake of PAH and TEA and tended to increase BUN. These results are similar to previous reports of NDPS-induced nephrotoxicity in Sprague-Dawley rats and suggest that either rat model would be suitable for future studies on the mechanism(s) of NDPS-induced nephropathy.