Nephrotoxicity of xenobiotics

Clinica Chimica Acta 237 (1995) 107-154

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Nephrotoxicity of xenobiotics Mario Werner *a, Michael J. Costa b aDepartment of Pathology, The George Washington University, Washington, DC, USA Department of Pathology, Unwersttyof Califorma, Darts, CA, USA b

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With the collaboration of Lloyd G. Mitchell, Ritu Nayar Department of Pathology, The George Washington University, Washington, DC, USA Received 6 June 1994; revision received 30 July 1994; accepted 30 July 1994

Abstract

Nephrotoxicity can be grouped by the xenobiotics place of action, by the clinical presentation or by the generic toxic effect. The latter can be dose related, indirect, idiosyncratic or allergic. Nephrotoxicity of lithium, demeclocycline, aminoglycosides, cyclosporine, mercuric ion, nonsteroidal anti-inflammatory drugs, methoxyflurane, ethylene glycol, D-penicillamine and methicillin is reviewed in light of all these three viewpoints, but emphasis is on toxic mechanisms. Keywords: Lithium; Demeclocycline; Aminoglycosides; Cyclosporine; Mercury; Nonsteroidal anti-inflammatory drugs; Methoxyflurane; Ethylene glycol; D-penicillamine; Methicillin

1. Introduction

T h e factors rendering any organ susceptible to the toxicity of a given xenobiotic are the substance's tissue specific distribution and selective accumulation, its tissue

* Corresponding author. 0009-8981/95/$09.00 © 1995 Elsevier Science B.V. All rights reserved. SSDI 0009-8981(95) 0 6 0 6 8 - O

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specific biochemistry or metabolic activation to a reactive toxicant as well as the organ's ability to repair the characteristic damage. Several unique physiological properties render the kidneys potential targets of drug toxicity: a disproportionately large blood supply, the ability to extract xenobiotics from blood, concentration of xenobiotics through water reabsorption as well as the counter-current mechanism as the glomerular ultrafiltrate passes through the nephron, and finally the urinary pH changes occurring in renal acid-base regulation. As a main consequence of these targeting circumstances the kidneys may accumulate xenobiotic concentrations well above those in other tissues. The drug metabolizing enzymes present in the kidneys, which are capable of biotransforming relatively inert chemicals to highly reactive metabolites include the cytochrome P-450 dependent mixed function oxidases, prostaglandin endoperoxide synthetase, glutathioneS-transferase, aminopeptidase, sulfotransferase, N-acetyltransferase, 3,-glutamyltranspeptidase as well as uridine diphosphate and uridine diphosphate glucuronyltransferase. The unequal intra-renal distribution of these enzymes represents a second targeting mechanism. Acute renal failure can result from damage to any part of the nephron, and is the most obvious and immediately dangerous form of drug nephrotoxicity. Estimates of the frequency of this therapeutic side-effect as the cause of acute anuria have varied as much as from 1:50 to 1:5 [1,2]. This discrepancy highlights the difficulty in recognizing drug toxicity as the cause of renal impairment, particularly in the presence of other risk factors. However, the kidneys should not be viewed simply as organs of excretion, but also as major effectors of homeostasis. Accordingly, drugs can cause a spectrum of renal syndromes other than acute failure. A comprehensive survey of the protean clinical presentations caused by the scores of nephrotoxic drugs in clinical use is beyond the scope of even an extensive review. Therefore, our purpose is simply to illustrate an embracing scheme by representative examples. Traditionally, nephrotoxic substances have been grouped by their place of action, where injury frequently is localized to specific cell types [3]. Such a classification may distinguish direct tubular injury (e.g aminoglycosides or mercury), acute interstitial nephritis (e.g. methicillin), decreased renal perfusion (e.g. cyclosporin), primary glomerulopathy (e.g. D-penicillamine), and obstructive nephropathy (e.g. ethylene glycol or methoxyflurane). However, the same drug may target toxic damage to different sites. For instance, non-steroidal anti-inflammatory drugs may cause decreased renal perfusion, primary glomerulopathy, interstitial nephritis or any combination of these. As a second alternative, drug-induced renal syndromes can be grouped by clinical presentation [4,5]. Such a classification may distinguish nephrotic syndrome (due to primary glomerulopathy), acute renal failure (due to prerenal events causing decreased renal perfusion, tubular necrosis, interstitial nephritis, intratubular obstruction or hemolytic-uremic syndrome), chronic renal failure (due to interstitial nephritis, glomerulosclerosis, nephrocalcinosis, obstructive uropathy or hypertension), disorders of acid-base, electrolyte and water homeostasis (due to altered potassium homeostasis, decreased free-water excretion, etc), and hemorrhagic cystitis. However, depending on clinical circumstances, the same drug may cause diverse renal presentations.

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A third possibility is to consider the generic toxic effect. Such a classification may characterize adverse reactions by five criteria: the frequency of occurrence, the dose relationship, the requirement of prior contact with the substance, the chemical specificity of the toxicity and its mechanism. By these parameters four types of adverse effects of foreign substances can be distinguished: dose related, indirect, idiosyncratic and allergic (Table 1). Our review of some of the better characterized nephrotoxic drugs combines the three described viewpoints. However, while morphology and clinical presentation are addressed, emphasis is on toxic effects. 2. Lithium

Introduced in 1949 as an antimanic drug in a paper published in The Medical Journal of Australia by Dr. John Cade, lithium carbonate originally was administered for limited periods of a few months [6-8]. However, maintenance lithium prophylaxis continuing for years is now the therapy of choice in recurrent manicdepressive psychosis [9]. The therapeutic window of the lithium ion is narrow, and acute intoxication may cause death, permanent disabling neurological sequelae or impaired endocrinological or cardiac function, but the main adverse effects are on the kidneys [10]. Polyuria and impaired renal concentrating ability without other nephrotic signs was first reported in 1970 [11], and is common in long-term lithium therapy without generally affecting glomerular filtration significantly [12]. Persistent nephrogenic diabetes insipidus, may occur even after discontinuation of lithium therapy [13]. Reports of chronic pathologic renal changes in animals [14] and humans [10, 15-17] treated with lithium also have appeared. Overall, the spectrum of lithium nephrotoxicity in man includes reversible concentrating defect, nephrogenic diabetes insipidus, hyperkalemia, hypercalcemia, distal renal tubular acidosis, acute renal failure, chronic interstitial nephritis, nephrotic syndrome and chronic renal failure [18-25]. Lithium is well absorbed when given orally, not bound to plasma proteins, and completely filtered in the glomerulus. About 80% is reabsorbed by a paracellular pathway in the proximal tubules [26], the remainder is excreted in the urine. Within a serum lithium concentration range spanning at least 0.05-2.0 mmol/1 [27], clearance and excretion fractions are independent of serum lithium. In rats, low sodium intake increases lithium toxicity, whereas high sodium intake prevents and reverses it by two mechanisms, first by blocking lithium reabsorption and so increasing clearance, and second by directly counteracting the toxic lithium effect on tissues and so increasing tolerance [28]. Sodium bicarbonate, and sodium thiosulfate not only compete for sodium reabsorption but also provide anions which promote obligatory excretion of lithium cations [27]. Osmotic diuresis and aminophylline administration increase lithium excretion by blocking reabsorption of sodium in the proximal tubule. A rat model showed that lithium interferes directly with the actions of antidiuretic hormone on cell membrane-bound proteins in the cortical portions of the distal tubule and collecting duct [12,26]. At a molecular level, lithium impairs antidiuretic hormone-sensitive adenylate cyclase, thereby decreasing the formation of intracellular cyclic AMP [25]. However, the fact that infusion of dibutyryl cyclic

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Table 1 Criteria defining five generic toxic mechanisms Dose related

Indirect

Idiosyncratic

Allergic

Frequency of occurrence

Variable, depending on agent

Variable, depending on agent

Related to genotype

Dose relationship

Yes

Yes

Yes, in susceptible individuals

Variable, depending on agent, genetic predisposition probable Erratic, response primarily determined by immunologicfactors in the individual Essential

Prior contact Not necessary with substance Chemical specificity Determined by chemical structure Mechanism

Examples

Not necessary Not necessary Determined by Determined by chemical chemical stucture structure

Antigen-antibody reaction, manifestations largely independent of agent Determined by Indirect Determined by Circulating chemical structure, chemical structure, antibodies or overcome by overcome by altered immunologic specific specific tissue response, antagonist antagonist antihistamines effective Lithium Methoxyflurane D-Penicillamine Methicillin Demeclocyline Chloroform Nonsteroidal Aminoglycosides Ethyleneglycol anti-inflammatory Cyclosporine drugs (%) Mercuric ion Mercuric ion (%) Nonsteroidal anti-inflammatory drugs

A M P was ineffective in countering lithium action suggests that it interferes with water reabsorption at a step beyond cyclic A M P formation. Lithium appears not to disrupt sodium transport in the ascending loop of Henle as does the fluoride ion, since the corticopapillary gradient remains preserved [10]. Even though severe nephrotoxicity has not been reported with well-controlled therapy [29], lithium induced diabetes insipidus, which remains unresponsive to antidiuretic hormone, is common. In an early study of 96 patients, polydipsia occurred in almost half of the cases and polyuria (defined as > 3 l / d a y ) in about one in ten cases. In almost all polyuric patients, maximum concentrating ability after dehydration and vasopressin was markedly impaired [12]. In another series of 57 psychiatric patients treated with long term lithium (7-year medium follow-up) three in four had decreased concentrating ability and about one in ten had decreased glomerular filtration [18]. In a third study of 46 patients treated for an average of 8 years, 85% demonstrated decreased concentrating ability and one in ten had a glomerular filtration rate below age matched controls [21]. A retrospec-

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tive trial of 153 patients found that glomerular filtration rate decreased slightly, as did renal concentrating ability, in subjects treated over 17 years [20]. A prospective trial of 46 patients followed while on lithium for 1-11 years and, after lithium was discontinued for 7 weeks to 26 months, concluded that renal concentrating ability and glomerular filtration rate eventually improved when lithium was discontinued. However, compared to age-matched controls, the patients recently taken off lithium showed decreased renal concentrating ability with normal glomerular filtration rate [19]. Another prospective trial carried out over periods of 6 months to 3 years found a mild reduction of renal concentrating ability in all lithium-treated patients, but the effect did not progress with time [30]. Finally, a recent survey of the literature estimates that about one-in-five unselected patients develop polyuria during lithium therapy, while about half of such patients show impaired urinary concentrating capacity [22]. Clinically, lithium-induced nephrogenic diabetes insipidus under the best circumstances inconveniences patients considerably and under the worst circumstances leads to life-threatening dehydration and electrolyte disturbances. The incidence of acute or chronic renal insufficiency, on the other hand, is rare following lithium therapy, but a causal relationship remains probable, and acute renal failure caused by lithium toxicity has been reported [22]. Slow release preparations, lower dosage, and simultaneous use of diuretics can improve urinary concentrating ability and can decrease both the reversible and the irreversible nephrotoxicity of lithium [31]. The therapeutic mechanism of the thiazides involves reduction of extracellular volume, causing decrease in glomerular filtration and increase in fractional sodium excretion with the paradoxical result of reduced polyuria. The potassium sparing diuretic amiloride, in addition, may counteract lithium's effect on the antidiuretic hormone itself [22,23,32]. Whether daily single rather than multiple dosing schedules equally are beneficial remains controversial [24,26]. The clinical dilemma between prescribing an adequate dose to control the psychiatric manifestations and a low enough dose to minimize renal or other adverse effects [33] demands the monitoring of serum lithium concentration. This precaution must now be considered mandatory in all those treated with lithium. Given the exclusively renal excretion of lithium, it is advisable to simultaneously measure serum creatinine. However, in all lithium-treated patients, regardless of the extent of polyuria, it is essential to prevent dehydration and subsequent lithium toxicity [24]. In confused or comatose patients, a reduced or absent anion gap may point to the latter [34]. When severe overdosage occurs, saline infusion can augment renal lithium ion clearance in hypovolemic patients, but in euvolemic patients hemodialysis is indicated. Renal biopsies in lithium-induced diabetes insipidus show vacuolization, ballooning and accumulation of diastase-sensitive, PAS-positive material in the cytoplasm of distal tubule and collecting duct epithelium [35-38]. Ultrastructural morphology evidences swelling of cytoplasm, atypical distribution of mitochondria and glycogen accumulation [36]. These lesions appear after 6 days on therapy, and usually are no longer demonstrable a month after termination of lithium intake. Indeed, lithiumassociated nephrogenic diabetes insipidus is presumed to be fully reversible.

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However, cases with persistent distal tubular atrophy and focal interstitial fibrosis or chronic tubulointerstitial nephritis have been reported among patients on long-term lithium therapy exceeding 1 year [13,37-41]. Distal tubular dilatation and cortical microcysts were prominent in these patients [36]. In a series of 14 cases with nephrogenic diabetes insipidus on chronic lithium therapy, renal biopsy showed pronounced focal nephron atrophy, interstitial fibrosis, or both in 13 cases [10]. Another series of 24 renal biopsies reports similar findings [18]. Chronic interstitial nephritis also was found long after termination of therapy in a few patients who had suffered from lithium induced diabetes insipidus [41]. While glomerular function in these cases generally remains unimpaired, lithium toxicity can also cause glomerular sclerosis. In the few cases who developed nephrotic syndrome, minimal change disease was found [42-44]. Overall, the rarity of all these cases has prevented clinical concerns [29-45]. Morphologic findings similar to those seen in man occurred in rats fed lithium carbonate for 3-18 weeks in doses corresponding to those used therapeutically [46]. Newborn rats fed 40 mmol/kg lithium, producing serum concentrations of 0.6-1.1 mmol/l, comparable to the human therapeutic range, developed chronic renal failure with polyuria and inability to concentrate urine. After 1 year of such treatment, renal histology showed pronounced tubular atrophy, cortical cyst formation and focal fibrosis [47]. In subacute lithium toxicity in rats, elevated levels of urinary lactate dehydrogenase, aspartate and alanine aminotransferases correlated with serum lithium levels, and continued to be elevated 10 days after lithium was discontinued [48]. In summary, long term lithium therapy causes polyuria and reduced renal concentrating ability by impairing the activity of antidiuretic hormone-sensitive adenylate cyclase in the distal tubule. This dose-dependent effect can be minimized by controlling dosage with monitoring of serum lithium concentration.

3. Demeclocycline In 1959, demeclocycline (7-chloro-6-demethychlortetracycline, declomycin) was introduced as a broad spectrum antibiotic. Demeclocycline is adequately, but incompletely absorbed from the gastrointestinal tract. About half of the drug in serum is protein bound, and the half-life is approximately 16 h. Two-thirds or more is excreted in the bile, the remainder in urine. Early pharmacologic testing of tetracyclines in rats had shown a slight diuretic action. However, this effect was not investigated further [49]. Clinically, it was subsequently established that tetracyclines can cause Fanconi syndrome as a result of one of three factors, namely excess dosage, use of degraded drugs, or use in patients with compromised renal function [50]. In addition, there have been sporadic case reports of tetracyclines causing acute tubular necrosis with nonoliguric renal failure in man [51,52], dogs and rats [53], much as interstitial nephritis in man [54]. In 1965, a first case of nephrogenic diabetes insipidus following 19 days of therapy with demeclocycline in usual dosage was reported in a 26-year-old male without otherwise impaired renal function [55]. The patient presented with con-

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However, such therapeutic use of demeclocycline should be reserved for patients in whom other modes of treatment are impracticable, since reversible acute renal failure following this medication has been reported [69-71]. Demeclocycline similarly can treat water retention effectively in hyponatremic cirrhotics. In this application, a close relationship between renal effects and serum drug concentration exists. However, in a series of seven cases who responded to the drug, five patients also developed progressive renal insufficiency, which resolved only 12-14 days after discontinuing treatment. This severe toxicity was attributed to the high serum drug concentrations (over 5 mg/ml in patients who responded to the drug, over 8 mg/ml in patients who developed renal insufficiency) caused by decreased biliary drug excretion given the hepatic impairment. Reduced renal function in these patients was correlated with an increase in urinary PGE 2, a decrease in urinary kallikrein, and a decrease in renal perfusion. However, no structural lesion of the glomeruli or renal tubules could be documented, and no evidence of renal parenchymal damage was evidenced by the urine sediment, the urine protein content, the urine microglobulin concentration or the quantitative urinary cast excretion [72]. The relationship between these observations and demeclocycline's effect on the distal tubule is not clear at this time. In summary, demeclocycline reversibly blocks antidiuretic hormone action by inhibiting adenylate c3~clase and protein kinase in the distal tubule, resulting in drug-induced nephrogenic diabetes insipidus without affecting other renal functions. This selective and dose-dependent effect can be used to treat inappropriate antidiuretic hormone secretion or hyponatremia in cirrhotics, but with high plasma drug concentrations and with decreased renal perfusion such medication may cause reversible renal failure.

4. Aminoglycosides Aminoglycoside antibiotics (gentamicin, tobramycin, amikacin, kanamycin, netilmicin) remain widely prescribed in serious gram-negative infections, even though well-controlled clinical trials have demonstrated that these drugs have an extremely low therapeutic index and that about one in twenty to one in ten courses of therapy produces acute renal dysfunction with a significant, but most commonly asymptomatic, increase in serum creatinine concentration 7-10 days after initiation of therapy [73,74]. However, the incidence of nephrotoxicity has ranged from less than 2% to almost 50%, with the highest incidences occurring in severely ill populations [75]. When acute renal failure occurs, it is generally nonoliguric. With termination of treatment, renal insufficiency usually is reversible, though it may persist for some time. Observations in humans as well as animals suggest that the same pathogenetic mechanism causes nephrotoxicity for all drugs within the class. However, the variable number of ionizable amino groups on different aminoglycosides, which are all highly positively charged at physiologic pH values, varies and net cationic charge correlates to a considerable degree with nephrotoxicity [76]. Streptomycin with only two free amino groups has limited, if any, nephrotoxicity. Gentamicin, tobramycin, amikacin, kanamycin and netilmicin, which have each five free amino groups, are potentially nephrotoxic, but can all be used systematically.

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Neomycin with six free amino groups is too nephrotoxic for parenteral use and has been administered only for irrigation, topically and as a bowel-sterilizing drug [74]. Aminoglycosides are bound less than 10% to plasma proteins. Protein binding, much as binding to cell membranes or bacteria, is inversely proportional to the ambient calcium concentration, as aminoglycosides compete with these ions for anionic binding sites. The positive molecular charge of these drugs prevents ready penetration of cell membranes, and aminoglycosides indeed appear to be only minimally metabolized. The primary elimination route of these very water-soluble molecules is renal. With molecular weights of about 500 Da, all aminoglycosides fall into the size range of compounds which are almost completely filtered by the glomeruli but not reabsorbed by the tubuli. Since there is also no significant tubular secretion, clearance is equal to or slightly less than that of inulin, and when glomerular filtration decreases, serum aminoglycoside concentration in blood rises proportionally. To avoid nephrotoxicity, therefore, dosing should be based on the glomerular filtration. Because of nephrotoxicity, general use of neomycin was discontinued before renal biopsy entered clinical use. Further, multiple variables can confound the investigation of aminoglycoside nephrotoxicity in patients with serious infections. Finally, acute tubular necrosis tended to be overdiagnosed in some autopsy studies [77]. Consequently, animal models have largely been used to elucidate the nephrotoxic mechanisms of aminoglycosides. Thus, even recognizing that extrapolation of findings between species demands caution and that animal studies use higher concentrations of drug than administered to man, the main conclusions about aminoglycoside effects on lysosomes, mitochondria and glomerular filtration derive from rat experiments. In the Lewis strain of rat, which is highly susceptible to gentamicin, this drug even produces acute tubular necrosis [78]. After a few days of aminoglycoside administration, the renal cortex progressively accumulates the drug achieving tissue concentrations exceeding blood concentrations many times. Once fixed by the kidney, release of aminoglycoside into urine is slow with a half-life of several days, far exceeding the original serum half-life which is less than 1 h in the rat and but a few hours in man. In various rat species, a suitable drug regimen can reproducibly cause a urinary concentrating defect and nonoliguric renal failure [79], mimicking human aminoglycoside nephrotoxicity. When further drug accumulation produces frank necrosis of tubular cells, the cortical drug concentration falls again. However, cellular regeneration occurs despite continued drug administration [79]. Micropuncture experiments in the rat have shown that fixation of aminoglycoside present in glomerular filtrate occurs mainly in a multistep uptake process through anionic phospholipid receptors located in brush border vesicles on the luminal surface of the proximal tubule and pars recta [80,81]. The mechanisms and regulatory factors involved in the membrane transport are not clearly understood, but the system is energy-dependent, and the competing presence of other aminoglycosides or increased luminal calcium ion concentration inhibit uptake [82,83]. On the other hand, if perfused rat kidney is rendered non-filtering, the cortical gentamicin concentration still attains about one fourth that of the control kidney [84], suggesting that aminoglycosides enter

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tubular cells also through their basolateral surfaces, even though luminal access predominates. Autoradiography of rat kidney has shown that, following receptor attachment, gentamicin undergoes pinocytosis and then is translocated to and accumulated in lysosomes, the prime targets of aminoglycoside toxicity [85-87]. Since this process requires oxidative cellular energy, it is prevented by either anoxia or metabolic inhibitors [87]. Animal and clinical observations support the concept that the mechanism of lysosomal damage is inhibition of phosphatidylinositol phospholipase C, causing a phospholipidosis within the proximal tubular lumen and eventually an enrichment of lipid material in the lysosomes themselves. At this latter stage, electron microscopy shows lysosomal swelling together with an accumulation of membranes of whorled material known as myeloid bodies [79,88,89]. The latter are not specific for aminoglycoside administration, and their presence does not indicate clinical toxicity. Labilization of the lipid laden lysosomes and intracellular release of potent hydrolases, or alternatively, depletion of one or more critical substrates due to impaired lysosomal catabolism are believed to cause the ensuing cellular dysfunction. While the sequence of this process remains hypothetical, the following observations support it. First, the nephrotoxic rank order among streptomycin, amikacin, kanamycin, tobramycin, gentamicin, and neomycin corresponds to the ability of these drugs to inhibit phosphatidylinositol phospholipase C [90]. Second, such other toxins to the proximal tubule as mercuric chloride induce neither the described biochemical nor morphologic changes. Third, aminoglycoside nephrotoxicity characteristically changes the urinary isoenzyme pattern of N-acetyl-/3-D-glucosaminidase to one reflecting lysosomal origin [91]. A second major toxic effect on the proximal tubule manifests itself in a decline of sodium potassium ATPase [92] with an attendant loss of intracellular cations such as potassium and magnesium [93]. Even short-term aminoglycoside infusion induces such electrolyte changes in auto-transplanted sheep kidneys [94]. The cause of this perturbation is believed to be impaired sodium and potassium permeability of the inner mitochondrial membrane, which in turn interferes with mitochondrial oxidative phosphorylation. In isolated mitochondria, aminoglycosides inhibit state 3 oxidative phosphorylation (ADP stimulated respiratory activity) while promoting state 4 oxidative phosphorylation (basal respiration). Again, the magnitude of this particular effect corresponds to the clinical nephrotoxic rank order among aminoglycosides [95]. Nevertheless, others have proposed that the impairment of sodium potassium ATPase is a direct toxic effect of aminoglycosides [96]. As a third major effect, and the central concern of clinicians, aminoglycosides can reduce glomerular filtration and cause renal failure. Scanning and transmission electron microscopy evidence a diminution in the size and number of endothelial fenestrae in the glomerulus, which reduces the sieving of lysozyme [97]. In the Wistar rat, up to 80% reduction in the density of endothelial fenestrae is reported [98]. Micropuncture in rats similarly shows decreased glomerular filtration for the entire kidney as well as for single nephrons. The effect is reversed both by administration of the angiotensin II inhibitor captopril or by a reduction of

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endogenous angiotensin through sodium administration, suggesting as its cause a hormonal mechanism rather than direct glomerular damage [99]. The pathogenic relationships between tubular alterations, on the one hand, and reduced glomerular filtration rate, on the other hand, remain as obscure in aminoglycoside nephrotoxicity as in acute renal failure seen in other experimental models of tubular necrosis [100]. Quantitative studies in rats receiving gentamicin showed significant decrease of the baso-lateral plasma membrane surface area in the proximal convoluted tubules, which correlated with the loss of renal function [101]. It has been popular to postulate tubular obstruction by necrotic cells as the cause of anuria [102]. However, in aminoglycoside toxicity the absence of significant cylindruria in the face of a significant drop in glomerular filtration, much as the absence of increased tubular pressure, argue against this explanation [103,104]. An alternate hypothesis invokes changed intra-renal hemodynamics with a shunting of blood from cortex to medulla. Gentamicin toxicity indeed decreases renal cortical blood supply, but no shift in flow from cortex to medulla occurs as in most other forms of oliguric acute tubular necrosis [105]. Instead, persistent perfusion of outer cortical nephrons may imbalance the glomerular-tubular blood supply in a small remaining number of filtering nephrons, and produce continued high urine flow in the face of a markedly depressed glomerular filtration rate. Thus, renal perfusion changes cannot fully account for the decreased glomerular filtration caused by aminoglycosides. Apart from the choice of agent, a large number of variables, including both dosing regimen and patient factors, have been analyzed as risk factors for aminoglycoside nephrotoxicity [76,106]. Parameters of the regimen considered important are cumulative dose, duration of therapy, type of administration (i.e. loading dose versus no loading dose, continuous versus intermittent), peak and valley blood concentrations and concurrent medications. While this list clearly implies a doserelated effect, the key parameter defining the toxic threshold has not been established. Patient parameters considered important are age, sex, obesity, renal disease, sepsis, hypovolemia and hypokalemia, and the factors generally agreed to reduce risk are correction of volume depletion and diminished renal perfusion, as well as dose adjustment for reduced renal function [75]. In summary, aminoglycosides target to the kidney as they are entirely cleared from blood by glomerular filtration, and given their positive charge bind to anionic sites on the proximal tubular lumen. Thence pinocytosis transports the drug to lysosomes and mitochondria. In lysosomes, aminoglycosides inhibit phosphatidylinositol phospholipase C, induce swelling through accumulation of myeloid bodies and presumably cause cell death by releasing lysosomal enzymes. In mitochondria, aminoglycosides inhibit state 3 respiration and increase inner mitochondrial membrane permeability, leading to decreased ATP production. This in turn decreases sodium-potassium ATPase function and causes intracellular electrolyte abnormalities. How tubular impairment causes the presenting clinical effect of decreased glomerular filtration remains speculative.

5. Cyclosporine Cyclosporine (formerly called cyclosporine A), a hydrophobic cyclic undecapep-

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tide produced by the fungus Tolypocladium inflatum, can be considered the prototype of a new generation of immunosuppressants that has revolutionized the management of allotransplantation. This drug specifically and reversibly inhibits immunocompetent T-helper lymphocytes by suppressing the interleukin-2 driven proliferation of activated T-cells [107,108]. Cyclosporine combines low myelotoxicity with effectiveness in preventing allograft rejection and graft versus host disease [109], as well as in the treatment of various autoimmune and ocular inflammatory diseases [110]. In addition, cyclosporine has been reported to have antischistosomal [111] and antimalarial activity [112]. Nephrotoxicity may accompany these potent therapeutic effects [113,114], a particularly unfortunate complication in managing renal transplants, limiting the more extensive use of this drug [115]. Nevertheless, use of cyclosporine has increased the 1-year survival of renal grafts by 10-20%, while almost eliminating the side effects of large-dose steroid administration [116,117]. Cyclosporine can be administered orally or parenterally. Gastrointestinal absorption occurs with a half-life of about 1 h. After a single oral dose of 600 mg, usually given hours before transplantation, peak serum concentrations occur within 3-4 h and vary about 5-fold (240-1250 mg/ml). Bioavailability varies from 20-50% (mean 34%) [118]. While erythrocyte uptake is 50%, 90% of the drug in plasma is protein bound, predominantly to lipoproteins. Lipid solubility and specific binding to cyclophillins confers a wide tissue distribution to cyclosporine and retards elimination. Rats given a single dose of tritiated cyclosporine showed highest radioactivity in liver, kidneys, adrenals, pancreas, thymus, thyroid and renal fat. Cyclosporine is metabolized extensively in the liver to at least 12 metabolites, all of which retain intact the cyclic oligopeptide structure of the parent drug [118]. The enzyme predominantly involved in these conversions is a cytochrome P-450-dependent monooxygenase system. Changes in hepatic monooxygenase activity are associated with a converse oscillation in cyclosporine nephrotoxicity, suggesting that the drug is detoxified by hepatic P-450 [117]. Terminal elimination of cyclosporine and its metabolites from blood or plasma occurs mainly in bile and has a half-life of 14-17 h [118]. Following oral administration, less than a tenth of the dose appears in the urine with only 0.1% of the dose unchanged cyclosporine [118,119]. Nephrotoxicity has been associated with cyclosporine use since its first clinical trials [113,120]. It can occur within a few days after renal transplant, if cyclosporine was given prior to transplantation [121]. Following renal transplant, serum creatinine typically rises less than 25% over baseline and usually responds to a decrease in cyclosporine dosage. Larger creatinine elevations are significant, because they are associated with permanent renal impairment in two-thirds of the cases. During the first 30 days after transplantation, about a third of these more severe elevations are due to acute rejection and usually show a rapid rise in creatinine, decreased urine volume and diffuse cellular infiltrates in renal biopsies [115]. However, acute rejection in cyclosporine-treated patients is uncommon, occurring in about one in ten cases of one reported series [115]. When any one of a number of antibiotics, including gentamicin, amphotericin B, cimetidine, erythromycin, ketoconazole, melphalan, ranitidine, tobramycin or vancomycin, is used together with cyclosporine in renal transplantation to combat the increased risk of infection due to

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immunosuppression, the combined toxic effect is greater than the additive effect [122,123]. Cyclosporine toxicity is dose-dependent [124]. With low-dose therapy, acute tubular nephrotoxicity is now seldom encountered, and most nephrotoxic effects are reversible when the dosage is lowered or discontinued [125,126]. However, chronic damage to renal allografts in the form of interstitial fibrosis and tubular atrophy due to cyclosporine microangiopathy still occurs [127,128], but these changes are difficult to assess as cyclosporine nephrotoxicity must be distinguished from graft rejection. The clinical dilemma confronted in this situation is whether to increase cyclosporine dosage or reduce and possibly discontinue it. Differentiation can be difficult, because no clinical or laboratory parameter is pathogenomic for either condition. Monitoring cyclosporine by radioimmune assay in needle aspiration biopsies of the allografl has been proposed, since drug concentration is expected to be elevated in nephrotoxicity and decreased in rejection [129], but this approach is prone to methodological artefacts and has not gained acceptance. Visualization of cyclosporine deposition in formalin fixed kidney biopsies by an antibody and using an avidin-biotin-complex immunoperoxidase technique could assist the differential [130], but this approach also has not proven clinically practicable. While it has been claimed that four deposition patterns correlated with clinical parameters of nephrotoxicity can be distinguished, confirmatory studies to localize cyclosporine at specific tissue sites in the kidney have been unsuccessful [131]. Serum B 2 microglobulin, finally, cannot distinguish nephrotoxicity and rejection as it is elevated in both, much as in cytomegalovirus infection [132]. Study of nephrotoxicity in the absence of the confounding variables seen in renal allografl has been possible in cyclosporine treatment of some autoimmune disorders. In 32 patients treated for autoimmune uveitis, urinary lysozyme remained unchanged, and the only nephrotoxic evidence was a mild decrease in glomerular filtration, a mild increase in the fractional excretion of magnesium and calcium along with mild increases in plasma uric acid and potassium [133]. No abnormalities of proximal convoluted tubule function as assessed by the absence of aminoaciduria, glucosuria, hypokalemia, hypophosphatemia or hypouricemia indicative of the Fanconi syndrome were seen. However, it must be borne in mind that cyclosporine causes dysfunction of the straight portion rather than the convoluted portion of the proximal tubule. Sustained hyperkalemia, out of proportion to reduction in the glomerular filtration rate, is frequently observed in cyclosporine-treated patients and is due partially to hyporeninemic hypoaldosteronism, partially to tubular insensitivity to aldosterone [129,134]. It may, additionally, reflect tubular injury, alterations in the juxtaglomerular apparatus or both [135]. In a study of 12 patients with rheumatoid arthritis, cyclosporine treatment decreased creatinine clearance by about a third, and increased urinary /32-microglobulin [110]. The latter change could not be explained by an elevation of serum /32 microglobulin above the renal threshold [110,132], and appears related to renal interstitial disease. Urinary N-acetyl-/3-glucosaminidase was not elevated, but urinary kallikrein excretion was decreased secondary to reduced renal blood flow. When cyclosporine was discontinued in six of these patients, renal function returned to baseline, but increased urinary

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fl2-microglobulin persisted. One case progressed to chronic renal failure with renal biopsy findings identical to those caused by cyclosporine toxicity in transplantation patients. Renal morphology was investigated in 17 patients with autoimmune uveitis treated for an average of 2 years with cyclosporine [136]. All biopsies showed increased interstitial fibrosis, tubular atrophy or both, but correlation between these changes and glomerular filtration was poor. Another study of six patients with various autoimmune disorders treated for 4-36 months with cyclosporine also evidenced changes in renal biopsies, namely focal interstitial fibrosis and tubular atrophy in five cases, arteriolar hyalinization in four and glomerular sclerosis in two [137]. Again histologic lesions correlated poorly with glomerular filtration, and the latter normalized in all but one case with extensive chronic tissue damage. Other histopathologic studies of renal biopsies from patients treated for various autoimmune disorders with cyclosporine stress such vascular changes as arteriolosclerosis with lumpy protein deposition of the media [124] and intimal proliferation with fibrin and platelet deposition [138] occurring despite the absence of longstanding hypertension [139] (Fig. 1). These findings suggest a definite risk for permanent renal impairment, and consequently cyclosporine treatment for such chronic conditions as autoimmune disorders or rheumatoid arthritis must be carefully evaluated [140].

Fig. 1. Cyclosporine nephrotoxicity demonstrating intimal proliferation in a small artery and hyalinization of an arteriole. These changes are indistinguishable from those seen in hypertension (hematoxylin and esosin, 200 ×).

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Extensive animal studies of cyclosporine nephrotoxicity have evidenced reversible vacuolization of the straight (S 2 and $3) segments of the proximal tubules and the appearance of inclusion bodies [141,142]. The former change results from dilation of the endoplasmic reticulum, the latter represents enlargement of autolysosomes. Microcalcifications and tubular regeneration are less constant findings. Interstitial fibrosis and tubular atrophy, alterations believed to be secondary to the cyclosporine associated arteriolopathy predominantly found in human kidneys [124], have not been reproduced in animal models. Thus, no experimental system which reflects the situation in man is available. The exact mechanisms of cyclosporine nephrotoxicity remain unknown. One hypothesis postulates that even though the morphological changes in the proximal tubule are the most useful markers of toxic change, the primary site of cyclosporine action is the preglomerular arteriole, where vascular tone increases in relation to drug dosage and blood concentration [143]. The resulting glomerular hypoperfusion is compensated by an autoregulatory mechanism to which both activated glomerular prostaglandin production and the renin angiotensin system contribute. Protracted cyclosporine exposure appears to exhaust glomerular prostaglandin synthesis for reasons which are not understood. A disequilibrium between reduced prostaglandin production and unaltered angiotensin II production then may impair the autoregulatory response, causing preglomerular vasoconstriction and leading to the observed fall in glomerular filtration. The joint occurrence of tubulotoxicity and preglomerular vasospasm suggests activation of tubuloglomerular feedback, but more likely the two toxic events are separate, the first of minor, the second of major importance. Interstitial fibrosis and tubular atrophy have been thought to result from the degeneration of single nephrons after arteriolopathy destroyed their supplying arterioles [138]. The facts that the chronic histologic findings and the arteriolopathy are unique to humans appear to support this hypothesis. However, a tubulotoxic effect occurring even from low cyclosporine doses, which does not become apparent histopathologically, but causes interstitial fibrosis over time, cannot be excluded [137]. In summary, cyclosporine clearly causes dose-related toxic effects, both on the straight segment of the proximal tubule, and on the preglomerular arteriole. Tubular toxicity, now seldom seen on low-dose therapy, has little functional consequence other than causing increased urinary/32 microglobulin excretion. The effect on preglomerular arterioles reversibly reduces glomerular filtration, and may lead to chronic arteriolopathy, which many believe to be the cause of eventual deterioration in renal function, renal interstitial fibrosis and tubular atrophy. 6. Mercuric ion

Mercury, which has long served as a diuretic, today is largely replaced by modem drugs as a therapeutic agent. On the other hand, mercury poisoning, just as lead poisoning, has developed from a rare occupational hazard to a serious environmental problem for whole populations. From a toxicological viewpoint, mercury can be divided into organic and inorganic agents. Among the latter, elemental mercury and divalent mercuric ion are the compounds of interest. The threshold limit value

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for mercury in air is 0.005 m g / m 3. In man, tightness and pain in the chest as well as difficulty in breathing results from inhalation of 1.2-8.5 m g / m 3 mercury. Air saturated with mercury contains 19.4 m g / m 3. Less than 0.1 g of mercuric chloride by mouth may cause severe symptoms, and 0.5 g may be fatal. One gram retained is always lethal. Organic mercury compounds vary markedly in toxicity. They can be divided into the relatively stable mercurials, such as methyl mercury and other short chain alkylmercury compounds, which are the most toxic forms of the element, and substances such as phenylmercury and methoxyalkylmercury from which the mammalian body rapidly liberates mercuric ions [144]. Elemental mercury is accumulated and stored in many tissues, but especially targets the brain. Exposure to mercury vapor causes lung dysfunction acutely, and central nervous system toxicity chronically. The latter is due to the passage of the lipid soluble elemental mercury across the blood-brain barrier into nervous tissue where it is rapidly oxidized to mercuric ion and so trapped. Short chain alkyl mercury compounds similarly concentrate within the brain, and clinically cause mainly central nervous system toxicity. On the other hand, mercuric ion does not cross the blood-brain barrier and is overwhelmingly concentrated in the kidney. Phenylmercury and other acylmercury compounds in vivo are rapidly converted to extracellular mercuric ion, whose toxicology their actions resemble. In particular, all organomercurial diuretics are acid labile and following rupture of the carbon chain release the mercuric ion. This instability may explain the potentiation of mercurial diuretics by acidifying salts. Intravenously administered mercuric chloride mostly binds to sulfhydryl groups both in plasma proteins and erythrocytes, leaving less than 1% available for glomerular filtration. Soon a fairly uniform distribution into all soft tissues, but not bone, ensues. After a few hours, about a quarter of the administered dose concentrates in the liver. Renal accumulation starts immediately and progresses until at 1 week, 90% of the remaining mercury load is found in the peripheral renal cortex, localized in the cells of the proximal convoluted tubule. The disposition of mercuric ion is triphasic and quite complex. The first excretion phase is mainly fecal and quantitatively corresponds to the mercury load originally deposited in the liver. After 4 days the first urinary excretion phase begins with a half-life of about 20 days. The remaining mercury is excreted in a second urinary phase with a half-life of about 100 days [145-147]. The mechanisms causing renal concentration are not fully understood. Two distinct processes are involved, that responsible for the location of mercuric ion in the renal cortex, and that responsible for the passage of mercuric ion from blood to the proximal tubular lumen where it is fixed. Since the glomerulus filters only the 1% of mercuric ion which is not protein bound, its plasma concentration increases markedly as glomerular water filtration occurs. This along with the circumstances that post-glomerular blood flow favors the renal cortex over the medulla was thought to determine the cortical enrichment and proximal tubular localization of mercuric ion. Evidence suggesting an essential role of an active transport of mercury from blood to the tubular lumen is the fact that pretreatment of rats by various toxins directed against the proximal tubules mitigates the subsequent effect of mercuric ion. This protection is most evident where pretreatment damage is greatest, and least effective in tubuli left intact [148]. Evidence suggesting selective

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tubular protein and mercury resorption is presented in a study of rats maintained on high protein diets, which showed significantly less renal accumulation of radiolabeled mercury and relatively little damage to the second segment of the proximal tubules compared to control rats [149]. However, the third segment of the proximal tubules, including the loop of Henle, exhibited the same degree of necrosis as in the control group. Metallothionein, an 11000-Da metal-chelating protein with a high cystine content synthesized in the liver and the kidneys, may play a role in the translocation of mercury. Prolonged exposure to either mercurial chloride or elemental mercury vapor induces the biosynthesis of metallothionein in the kidney, but not in the liver [150-152]. Renal fixation of a single mercury dose has an upper limit, possibility dependent on the available metallothionein. With an increasing dose, both the relative amounts of mercury deposited in the kidneys and complexed by metallothionein decrease with a simultaneous rise in urinary mercury excretion [153,154]. To be effective as a diuretic or acutely nephrotoxic agent, mercuric ion must bind to sulfhydryl groups on cell membrane proteins of the distal part of the proximal tubular lumen [155]. Experiments, showing that albuminUria in rats [156] and hemoglobinuria in dogs [157] protect against toxicity by offering mercuric ions alternative binding sites, support this concept. In cell suspensions, much as in experiments with frog skin and liver slices, the mercuric ion has been shown to inhibit the sodium-potassium ATPase [158]. In the complex anatomical arrangement of the kidney tubule, mercuric ion in this fashion somewhat selectively blocks the reabsorption of sodium by inactivating the sodium battery driving this process, diuretic action results. The impairment is specific for reabsorption of sodium while the reabsorption of ammonia and other substances proceeds normally. When the tubular mercuric ion concentration rises from pharmacologic to toxic, complete denaturation of the sodium-potassium ATPase and of other membrane proteins results. In addition, mercuric ions now also bind to phospholipids, thereby disrupting the membrane, as well as to nitrogenous bases, thereby inhibiting protein synthesis [159]. Chemical alteration of phospholipid composition of plasma membrane is seen [160], leading to increased membrane permeability. As the renal tubular cells take on more sodium while losing potassium, they begin to swell. Mitochondrial function is also impaired [161,162]. The final mechanism for cell death may be an uncontrolled flux of calcium ions into the cells, which is toxic to mitochondria and activates lysosomal enzymes. Within 12-24 h after administration of HgC12 in rats, there is significant correlation between rising blood urea nitrogen, increased intraceUular calcium concentrations and lethal cell injury, as determined morphologically [163]. At this point, histology shows degeneration, fragmentation and necrosis of tubular epithelial cells (Fig. 2). The basement membrane may have lost functional integrity while casts and granular debris often block the tubular lumen. Mercuric ion also has been shown to produce adverse effects in calcium-dependent cell signaling in an in vitro cell system, as the mercuric ion can replace the calcium ion on the regulatory sites of proteins, interact with functional enzyme groups, and interfere with signal transduction, calcium channels and pumps [164]. This may impair the ability of the cell to respond to stimulation by hormones and

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Fig. 2. Mercury associated acute tubular necrosis (early phase) showing necrotic proximal tubules containing desquamated cells and cellular debris in the lumen (hematoxylin and eosin, 200 × ).

growth factors and may result in the loss of important cellular functions or activation of mechanisms that compromise cell survival. Clinically, the ultimate outcome of acute mercuric ion poisoning is anuria, but the mechanism of this effect is not clear. Commonly, cessation of urine flow has been ascribed to tubular obstruction. However, experimental evidence is conflicting. Rather than increased intratubular pressure, expected as a result of blockage, micropuncture studies in rats actually found decreased pressure, suggesting reduced glomerular filtration [165]. Others observed a normal inulin clearance at the level of the proximal tubule, and therefore, ascribed anuria to back diffusion through the tubular epithelium [166]. Still others found that the clearances of inulin and mannitol were equally reduced in mercuric ion-induced anuria of the rat. Since tubular back diffusion following obstruction would have removed the smaller mannitol molecule faster than inulin, this mechanism was rejected and anuria was ascribed to reduced filtration caused by preglomerular vasoconstriction [167]. No systematic investigation of renal biopsies obtained in the course of nephrotoxicity has been published, and no ultrastructural studies in man are available. Based on autopsy findings [168] and clinical observations [169], the histopathology of acute mercury nephrotoxicity depends on the elapsed time. At 3 days, extensive and diffuse cell necrosis affects the proximal tubules selectively. Desquamated cells and cellular debris fill the tubular lumen. The basement membrane remains intact.

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At 7-9 days, necrotic debris has almost disappeared from the tubules, but the proximal tubules are dilated and lined by a flat, basophilic epithelium. By 2 weeks the latter becomes cuboid. Altogether different mechanisms involve the kidney as the target of chronic mercuric ion toxicity, which expresses itself as proteinuria, the nephrotic syndrome, and in the morphological pattern of membranous glomerulonephritis (Fig. 3). To explain the formation of immune complexes and the damage to the glomerular basement membrane in this situation, two mechanisms have been proposed. Either, the mercuric ion may combine with a blood protein to form a hapten complex and subsequent antibody production then allows the formation of immune complexes. Alternatively, antibodies may be formed against tubular antigens released into circulation after direct tubular damage [170]. In rats, mercuric chloride administration induces anti-glomerular basement membrane antibodies [171]. The pathological alterations of mercury induced autoimmunity resemble those of chronic graft versus host disease, where excessive activation of T cells causes secondary activation of B cells, which produce antibodies, especially systemic lupus erythematosus-like autoantibodies of the IgG isotype. All autoimmune phenomena induced by mercuric chloride in rats are T cell dependent, since they fail to develop in athymic rats. The observed immunopathological alterations, induced by exposure to mercury compounds in humans, have occurred in cases of relatively short exposure to high concentrations of mercury [172-175].

Fig. 3. Mercury associated immune complex glomerulonephritis in mouse. Left panel: Immunofluorescent granular immunoglobulin deposits on the walls of glomerular capillaries (IgG immunofluorescence, 250 ×). Right panel: Electron dense subepithelial and intramembranous deposits (transmission electron micrograph, 5000 × ).

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Currently there are several urinary enzymes which have been proposed to detect early damage in the kidney induced by mercury and other nephrotoxins, long before routine measures of renal function, such as serum creatine, become abnormal. Increased N-acetyl-/3-D-glucosamidase (NAG) has shown promise as an indicator of early tubular cell injury [176,177]. In the kidney, intestinal type human alkaline phosphatase is found exclusively in the brush border of the tubuloepithelial cells present in the S3-segment of the proximal tubule and has been suggested as a highly specific and sensitive marker for nephrotoxic effects at this location [178]. In summary, the characteristic distribution of particular classes of mercury compounds determines the toxicity spectrum of this element. The kidney becomes the target of acute mercuric ion toxicity as a consequence of the selective distribution of this agent to the luminal surface of the proximal tubules, and the inhibition of sulfhydryl containing enzymes at that site. The kidney may also be damaged by immune mediated mechanisms after exposure to mercuric ion.

7. Non-steroidal anti-inflammatory drugs Over 20 new non-steroidal anti-inflammatory drugs (NSAID) have been introduced in the last three decades with a number available 'over-the counter' [179,180]. All these agents inhibit the initial step of prostaglandin synthesis from arachidonic acid, which is catalyzed by cyclooxygenase (Fig. 4). Aspirin (acetyl salicylic acid) acetylates cyclooxygenase irreversibly. In contrast, such newer NSAIDs as indoleacetic acid derivatives (e.g. indomethacin), propionic acid derivatives (e.g. ibuprofen) and efenamic acid derivatives (fenamates) inhibit cyclooxygenase reversibly. The entire class of drugs, although well tolerated and considered safe, causes a transient decrease in renal function in perhaps one in five patients [181], and prolonged excessive use of all of these has been recognized as an important contributing factor in the development of chronic renal disease. Defini-

PHOSPHOLIPIDS CORTICOSTEROIDS

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PHOSPHOLIPASE ARACHIDONICACID

NONSTEROIDAL ANTIFLAMMATORY AGENTS

CYCLOOXYGENASE

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PROSTAGLANDIN ISOMERASE PROSTAGLANDIN (PGE2,PGF2,ECT)

THROMBOXANE SYNTHETASE . THROMBOXANEA2

PROSTACYCLIN SYNTHETASE PROSTACYCLIN

Fig. 4. Biosynthetic pathway for prostaglandins.

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tive comparative epidemiological studies assessing the relative frequency of toxicity of these drugs are lacking, but sulindac and the non-acetylated salicylates appear to have fewer adverse renal effects [182-184]. Just like their anti-inflammatory effect, the main nephrotoxic effects of NSAID derive from the inhibition of prostaglandin synthesis [185]. Accordingly, all NSAID appear to impair renal function in two pathophysiologic conditions, first primary kidney disease and second abnormal circulatory homeostasis, where a normal kidney functions as if in a state of sodium deprivation [186-188]. In addition, these drugs may also cause papillary necrosis, interstitial nephritis, nephrotic syndrome, hyporeninemic hypoaldosteronism or the inappropriate antidiuretic hormone syndrome. All NSAID are well absorbed orally. Since the number of these agents precludes discussion of their individual metabolism, just illustrative examples of each drug class must suffice. Eighty percent of aspirin is conjugated with glycine in the liver and then excreted in the urine. As this pathway is saturable, a small dose increase may produce a large increase in blood drug concentration [189]. The indoleacetic acid indomethacin is demethylated and deacetylated in the liver with subsequent excretion of both the inactive metabolites and unchanged drug in bile and urine [190]. The indoleacetic acid sulindac, given as the sulfoxide, is metabolized by the liver cytochrome system to the sulfide, the active agent. Eliminated in the bile, the latter is subject to enterohepatic circulation providing for a longer triphasic half-life [191]. The propionic acid ibuprofen is mostly metabolized in the liver with a half-life of approximately 3.5 h, while less than a tenth is excreted unchanged in urine and bile [192]. Mefenamic acid similarly is mostly metabolized in the liver with a half-life of about 4-6 h [180]. Glomeruli, renal arterioles, collecting tubules and the renal medullary interstitium convert arachidonic acid de novo to prostaglandins [193,194]. The kidney has the enzymatic machinery to synthesize vasodilatory prostaglandins (PGE 2, PGI 2, PGD 2) as well as vasoconstrictor prostaglandins (endoperoxide, thromboxane A2, PGF 2) [195]. These eicosanoid compounds have been implicated in the regulation of a variety of renal functions including blood flow, glomerular filtration, water excretion, sodium excretion, renin and erythropoietin release [194]. Production of the different prostaglandins along the nephron follows a specific pattern, which permits modulation of renal function by local rather than systemic homeostasis. Indeed, urinary prostaglandin excretion is elevated in response to diuretics [196], increases up to 5-fold in congestive heart failure [197], and up to 6-fold in cirrhosis and ascites [198]. The view that prostaglandin synthesis is cytoprotective is supported by the observation that under normal, euvolemic conditions, experimental inhibition of renal prostaglandin synthesis affects nephron function little, whereas in fluid or electrolyte depletion the same inhibitory effect becomes important [186-188]. Clinically, NSAID become nephrotoxic when inhibition of prostaglandin synthesis compromises adaptation of renal blood flow and glomerular filtration to renal stress [194]. Humoral regulation normally adjusts glomerular function by controlling the afferent arteriolar tone and the filtration surface through glomerular mesangial contraction. When increased angiotensin II stimulates mesangial con-

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traction in renal stress, prostaglandins oppose this pressor action and so maintain adequate glomerular blood flow. Consequently, the constancy of glomerular pressure and filtration requires a regulatory balance [196]. For instance, urinary prostaglandin excretion increases in sodium deprivation in parallel with stimulation of the renin-angiotensin system [188]. When cyclooxygenase inhibitors remove the check prostaglandins exert on angiotensin II, glomerular filtration decreases in certain physiologic situations, say dietary sodium restriction, as well as in certain pathologic conditions, say congestive heart failure [199]. Renal prostaglandin production is also believed to participate in the adaptation to loss of renal mass. Thus, creatinine clearance and urinary PGE 2 correlate inversely in patients with chronic glomerulonephritis or interstitial nephritis [200], and elevated urinary or serum thromboxanes or prostaglandins have been reported in a variety of renal diseases [201]. The most common effect of NSAID on the kidneys is a reversible functional disturbance, caused by diminished renal blood flow and enhanced tubular reabsorption of sodium chloride [193], but the renal pathology associated with these drugs may be wider than generally recognized, and concomitant disease may confound recognition of renal drug reactions, when azotemia, hyperkalemia, decreasing urine output and increasing body weight would suggest it. Therefore, diagnosis relies mainly on the temporal relationship to NSAID administration. In addition to renal dysfunction secondary to altered hemodynamics, NSAID can cause tubular necrosis or acute interstitial nephritis. Following cessation of therapy, reduced natriuresis or renal insufficiency usually is completely reversible within 1-3 days, in the first case, but slow in the latter two situations. Continued NSAID administration can precipitate acute renal failure as well as life threatening hyperkalemia in adults [202], much as irreversible renal failure in children with corticosteroid resistant nephrosis [203]. Shock, congestive heart failure, parenchymal renal disease, nephrotic syndrome, immune disease involving the kidneys, cirrhosis with ascites, diuretic use or general anesthesia enhance the risk of NSAID nephrotoxicity, supporting the concept of a special prostaglandin role in renal stress [198,201]. Particular caution is necessary when using NSAID following renal transplantation, since both reduced renal functional mass and immune disease activity have to be taken into account [204]. Other risk factors for NSAID nephrotoxicity include advanced age [205], contracted intravascular volume due to nephrotic syndrome or ascites, low cardiac output, atherosclerotic cardiovascular disease, preexisting renal dysfunction, or acute gouty arthritis [188]. Patients chronically taking compound NSAID [206] or NSAID in association with indomethacin, phenylbutazone [207], ibuprofen [208] or fenoprofen [209] have been reported to develop chronic renal insufficiency due to the development of papillary necrosis, although occasional cases have been related to aspirin use alone [206]. The initial lesion includes necrosis of the fine structures of the medulla such as the capillaries, the thin loops of Henle and interstitial cells. Subsequent degenerative change of other structures follows a typical multi-stage pathology, eventually affecting the renal cortex once the entire medulla is compromised. At this stage, hyaline casts, tubular dilatation, glomerular and tubular sclerosis, fibrosis, scarring and pyelonephritis are seen. Just as clinical cases have been

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reported both in children [210] and adults [209], pre-clinical testing of most newer NSAIDs has documented papillary necrosis in rats [211]. Irreversible renal failure without papillary necrosis while on NSAID also has been described. Animal models [212] as well as clinical experience [195] suggest that papillary necrosis relates to inhibited prostaglandin synthesis in the renal medulla. However, the pathologic perturbation may involve more than impaired PGE 2 production, and such mechanisms as countercurrent concentration delivering a 'papillotoxin' or microvascular occlusion have been postulated [212]. On the other hand, the risk factors for papillary necrosis, namely advanced age, cardiovascular disease and volume depletion [188], again argue for a connection between prostaglandin function and the 'stressed kidney'. Hyporeninemic hypoaldosteronism (causing hyperkalemia) and syndrome of inappropriate antidiuretic hormone action (causing hyponatremia), still other pathophysiologic alterations associated with NSAID therapy, are also believed to be due to intra-renal inhibition of prostaglandin synthesis. Supporting this hypothesis, nephrogenic diabetes insipidus improves with NSAID therapy [188]. A number of cases of acute interstitial nephritis, histologically similar to that seen in antibiotic induced allergic interstitial nephritis, and clinically manifested by acute renal failure, have been associated with use of phenylbutazone, tolmetin, zomperic, indomethacin and diflunisal [188,213-216]. This adverse effect typically affects older people after NSAID exposure of about half a year (range two weeks to 15 months), and fenoprofen is the usual causative agent (over half the cases) [188,217]. Contrasting with other forms of acute interstitial nephritis, nephrotic syndrome [218] occurs in two out of three cases, while such other hypersensitivity manifestations as eosinophilia, rash, fever and arthralgia only occur in one out of five patients [213]. Clinical presentation includes edema, hypertension, nephrotic range proteinuria (mean excretion over 10 g/day) and hypoalbuminemia (mean serum albumin about 2 g/dl). After discontinuation of NSAID, the long-term course typically is favorable with eventual complete recovery in a period of a few weeks up to a year. However, cases which required corticosteroids before renal function returned have been reported [219], and in some patients proteinuria and reduced glomerular filtration may persist. In one series, renal biopsy showed normal glomeruli, immunofluorescent studies were negative or nonspecific, and electron microscopy showed glomerular epithelial cell foot process fusion [217,220,221] (Fig. 5). In another series, all of 22 patients with both nephrotic syndrome and renal failure showed either focal or diffuse tubulointerstitial nephritis with mononuclear cells of the lymphocyte type predominating, while eosinophils were seen in only a third of the biopsies and were not prominent [188] (Fig. 6). Two of four other reported cases of nephrotic syndrome without renal failure included in that second study showed no interstitial nephritis, but the focal nature of the disease may explain this absence of findings. In this form of adverse NSAID reaction, evidence of tubular atrophy, necrosis and dilatation generally correlates with the degree of renal insufficiency [188,217]. The pathogenesis of NSAID induced combined nephrotic syndrome and interstitial nephritis remains unknown. 'Drug hypersensitivity' has been suggested, but in addition to the distinct clinical presentation drug exposure was much longer than

Fig. 5. Nonsteroidal anti..inflammatory drug associated nephrotic syndrome. Left panel: Normal glomerulus by light microscopy (hematoxylin and eosin, 400 × ). Right panel: Electron microscopy of glomerulus showing podocyte foot process fusion. Basement membrane is unremarkable and without electron dense deposits (transmission electron micrograph, 7000 x ),

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Fig. 6. Nonsteroidal anti-inflammatory drug associated interstitial nephritis showing lymphocytes in edematous interstitium and tubular lumen (hematoxylin and eosin, 1000 × ).

characteristic for hypersensitivity (months rather than days) [188,217]. Furthermore, nephrotic proteinuria is not typical of hypersensitivity interstitial nephritis. Some investigators postulate a cell-mediated immune response, and a predominance of T cells in the interstitial infiltrate has been documented in two cases [219], while another study in contrast has found fewer eosinophils but more B cells and plasma cells [222]. The fact that this syndrome occurs predominantly in the elderly, who are more susceptible to dose-related toxicity, has led others to hypothesize that a direct toxic effect on the glomerular epithelial cell causes the nephrotic syndrome. In summary, all NSAID block renal prostaglandin production, which is essential to blood circulation in the 'stressed kidney'. Decreased glomerular blood flow impairs renal function and can lead to acute renal failure. NSAID-induced papillary necrosis, much as the occasionally seen hyporeninemic hypoaldosteronism and the inappropriate antidiuretic hormone syndrome probably also are secondary to the described enzyme blockage. The mechanism of the interstitial nephritis associated with nephrotic syndrome is not completely understood, but probably not analogous to the allergic interstitial nephritis caused by methicillin.

8. Methoxyflurane Introduced in 1960, methoxyflurane (Penthrane R) was one of the first fluorinated ethers used as a general anaesthetic [223]. While this drug possesses desirable

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properties, in particular a potent analgesic effect, associated adverse effects have reduced its use markedly [224]. The first three cases of methoxyflurane nephrotoxicity, including two with lethal outcome, were observed in 1964 [225]. Shortly thereafter, 16 cases of nephrotoxicity among 94 surgical patients in which the drug was utilized were reported [226]. The clinical syndrome comprised polyuria (up to 4.0 1/day), a negative fluid balance, dehydration, pronounced weight loss, hypernatremia, elevated serum osmolality and blood urea nitrogen. Urine osmolality remained close to that of serum and responded poorly to challenges by fluid deprivation or antidiuretic hormone administration [226]. The same syndrome, clinically identical to nephrogenic diabetes insipidus, subsequently has been described in others receiving general methoxyflurane anesthesia [227], in a subject who abused the drug [228] and in medical personnel occupationally exposed to this agent [229]. Methoxyflurane is extensively metabolized in the liver by isoenzymes 2 and 5 of the cytochrome P-450 system, a family of enzymes limited primarily to the $2 and $3 ceils of the proximal tubule and normally responsible for detoxification. Both isoenzymes involved are inducible by phenobarbital and require cytochrome b-5 for activity [230]. The following reaction releases fluoride and dichloroacetic acid when methoxyflurane is o-demethylated: C C I 2 H C F 2 O C H 3 --~ C C I 2 H C O O H + 2 F - + C H 2 0

Fluoride ion is believed to be the important nephrotoxic product, since the severity of the polyuria correlates with the plasma fluoride concentration [231,232]. Dichloroacetic acid is metabolized further to oxalate, and calcium oxalate crystals have been observed in kidneys of patients suffering from post-methoxyflurane nephrotoxicity [233-235] to which they could contribute as an additional cause in some cases [233,236]. However, by itself, oxalate produces anuria not polyuria. Trials with methoxyflurane in Fischer 344 rats capable of biotransforming methoxyflurane to inorganic fluoride showed dose-related nephrotoxicity, characterized by antidiuretic hormone resistant polyuria, weight loss, elevated serum osmolality, sodium and urea [231]. Urinary sodium, potassium, osmolality and urea nitrogen concentrations fell in proportion to the administered dose, while serum inorganic fluoride concentrations similarly increased in proportion to the dose. The severity of the syndrome and plasma fluoride concentration increased following induction of hepatic mixed function oxidases. When very high methoxyflurane doses were administered to these rats, changes in renal morphology were unspecific and primarily localized in the proximal tubules. The nephrotoxic effects could not be duplicated in other murine strains, but injection of inorganic fluoride produced renal changes resembling those seen after methoxyflurane administration [237], namely a prompt decrease in the renal medullary concentration gradient, increased urine flow and sodium excretion together with decreased urine osmolality and free water reabsorption. These aggregate findings duplicate the observations in patients with methoxyflurane nephrotoxicity associated with increased fluoride concentrations [238,240]. The proposed mechanisms of fluoride-induced polyuria include inhibited salt and water reabsorption in the proximal tubule and in the thick ascending limb of

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Henle's loop, increased blood flow to the renal medulla and decreased responsiveness of the collecting duct to antidiuretic hormone [232]. It must be noted that the most obvious impairment of nephron function occurs distal to the proximal tubule where fluoride causes histological change [231]. Intravenous infusions of sodium fluoride in rats dissipates the osmotic gradient in the renal medulla and causes a sustained dose-related increase in fractional sodium excretion and urine flow [232,241,242]. These findings suggest that NaF inhibits NaC1 reabsorption in the ascending limb of Henle's loop. Supporting this conclusion is the observation that NaF decreases short-circuit current in the bullfrog cornea, which has been used as a model of the mammalian thick ascending limb of Henle's loop, since it selectively transports chloride ions [232]. When the solute concentration in the renal medulla approaches that of plasma and the osmotic medullary gradient is reduced during water diuresis, NaF does not affect water clearance in rats. Although the renal medullary fluoride was not measured in these experiments, failure to achieve a sufficient medullary NaF concentration to inhibit chloride transport may explain the lack of effect. In normally hydrated rats, renal medullary fluoride concentrations may exceed plasma concentration 7-fold [242]. The toxic targeting to the ascending limb of Henle's loop partially must be due to this selective localization [232]. As evidenced by experiments comparing the effect of furosemide, which functions solely at the ascending thick limb of Henle's loop, with that of NaF, the latter also appears to affect a more distal tubular site, since free water clearance with NaF exceeds that seen with furosemide at equinatriuretic doses. Further, fluoride inhibits antidiuretic hormone induced increases in medullary cyclic AMP and reduces basal medullary tissue content of the nucleotide [232]. Thus, fluoride appears to inhibit water reabsorption directly by a mechanism independent of its effect on the medullary osmotic gradient. In support of this hypothesis, others have shown decreased urinary cyclic AMP in sodium fluoride-treated rats [243]. Fluoride is known to inhibit intermediate metabolism, particularly anaerobic glycolysis [244]. In the renal medulla, high fluoride concentrations may inhibit enolase, and thereby reduce the energy supply for solute transport and cyclic AMP production [245]. At least partly, a common mechanism, therefore, may underlie the multiple apparent renal actions of fluoride [232]. In summary, methoxyflurane catabolism in the liver releases fluoride ion. The latter causes dose-dependent nephrotoxicity and should be monitored following methoxyflurane exposure [228,229,246]. Fluoride causes dysfunction in the distal tubule, primarily by inhibiting NaCI transport in the ascending thick limb of the loop of Henle. In addition, fluoride inhibits the cyclic AMP response to antidiuretic hormone. Inhibition of glycolysis due to inactivation of enolase appears to be the mechanism for both fluoride actions.

9. Ethylene glycol Ethylene glycol is a colorless, odorless, relatively non-volatile liquid which has a boiling point of 197°C [247], and is completely miscible with water. This substance has many commercial applications in detergents, paints, lacquers, polishes, phar-

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maceuticals, and as a substitute for glycerine in cosmetics [248], but is used most commonly as a de-icer and antifreeze in internal combustion engines. Ethylene glycol toxicity was first observed in the Second World War, when this liquid erroneously was substituted for coffee water in a German military camp [249]. In addition to its ready availability, the compound's viscosity and warm, sweet taste may have contributed to its popularity as a poor man's substitute for ethanol or as a suicide agent [250]. Ethylene glycol ethers, such as ethylene glycol butyl ether, an ingredient in many window and glass cleaners, produce equal if not more toxicity in experimental animals than ethylene glycol itself [251]. The minimal lethal ethylene glycol dose is 1.4-1.6 ml/kg or about 100 ml for the average adult. Ethylene glycol itself is not toxic, but is metabolized by the liver and kidneys into toxic derivatives (Fig. 7) [252]. Oxalate, a major toxic metabolite, has a lethal dose of 0.1 g/kg [253]. In the Rhesus monkey, which should closely reflect human conditions, the plasma half-life of ethylene glycol is 3 h [254]. In the same animal, during 24 h following administration of 1 ml/kg ethylene glycol, 20% is recovered unchanged in urine, and only 1% as oxalic acid. Since the latter compound is not significantly metabolized, its elimination depends solely on the ethylene glycol dose and on renal excretion. With increasing substrate concentration, the relative fraction converted to oxalate increases, suggesting rate-limited decarboxylation and transamination by alternate pathways [248]. Clinically, ethylene glycol intoxication manifests itself in three distinct, dose-related stages [233]. In a first stage, lasting 30 min to 12 h following ingestion, neurological pathology dominates. The patient appears intoxicated and may suffer

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Fig. 7. Metabolic pathway for ethylene glycol.

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from nausea, vomiting, convulsions and even coma. Common physical signs are nystagmus, ophthalmoplegia, papilledema, depressed reflexes and tetanic contractions [255]. These manifestations relate to the aldehyde metabolites which attain peak concentrations 6-12 h after ingestion. Glycoaldehyde, glyoxal, glycolate and glyoxylate inhibit oxidative phosphorylation, glucose metabolism, protein synthesis, DNA replication and ribosomal RNA synthesis [248]. Laboratory analyses at this stage show moderate leucocytosis (10000 to 40000 white blood cells/mm3), hypocalcemia, metabolic acidosis with increased anion gap and spinal fluid findings compatible with meningoencephalitis [255,256]. Urinalysis should reveal the excretion of characteristic needle-shaped, birefringent monohydrate crystals of calcium oxalate [257]. Repeated examination may be necessary, since formation of the characteristic forms may be delayed [258], and in anuric patients bladder wash and examination of the sediment may increase the chances of detecting crystalluria [259]. In a second clinical stage, starting 12-24 h after ingestion, cardiopulmonary manifestations predominate as tachycardia, mild hypertension, pulmonary edema, coma or possibly congestive heart failure supervene. The pathophysiology of these symptoms is not well understood, but widespread capillary damage is assumed to be the primary lesion. Death from pulmonary edema, bronchopneumonia or cardiac dilation with disseminated petechial hemorrhages may ensue between 24 and 72 h following ingestion [248,260]. Some investigators have stressed the importance of a bicarbonate-resistant metabolic acidosis as a primary mechanism causing the abnormalities of this second stage [261]. Indeed, kidney damage and outcome correlate with the severity of acidosis, which always develops in severe cases, but not with serum ethylene glycol concentration [262]. Acidosis is due to both glycolic and lactic acid, with the former resulting directly from the conversion of ethylene glycol [263], and the latter from an increased ratio of reduced to oxidized nicotinamide adenine dinucleotide produced during the oxidation of ethylene glycol by alcohol dehydrogenase [256]. Just as following ethanol consumption, these conditions drive the lactate dehydrogenase reaction toward lactate. The metabolites of ethylene glycol, on the other hand, are not primary contributors to the high anion gap, even though the abundant crystalline forms of oxalic acid in the urine continue to assist clinical diagnosis at this stage [264]. The relevance of these insights is that prompt recognition and correction of acidosis and hypocalcemia have decreased mortality in the second stage of intoxication [248]. Patients who survive the initial 3 days of intoxication enter the third stage where renal damage due to oxaluria becomes manifested and the severity of renal failure determines the clinical course. No systematic study of renal pathology in ethylene glycol poisoning exists, just as no ultrastructural studies have been reported. Morphologic information about human nephrotoxicity comes from autopsies [265-267]. Histologic examination of the kidney in these cases reveals the presence of intratubular crystals, dilated proximal tubules and degeneration of tubular epithelium (Fig. 8). Large numbers of light yellow crystals arranged in sheaves, rosettes or prisms are almost pathognomonic for the oxalateexcretion of ethylene glycol intoxication. Under polarized light, the crystals are brilliantly birefringent

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[268]. Some crystals, mostly in proximal tubules, may be intracellular. Further, distal tubular degeneration is usually present, albeit less pronounced. Interstitial inflammatory loci and edema are noted, but glomerular damage is not prominent. The aggregate of these changes is usually reversible, but tubular atrophy and interstitial fibrosis may result in permanent renal insufficiency. Uni-nephrectomy increases the vulnerability of the remaining kidney to such lithogenic risk factors as ethylene glycol intoxication [269]. Even though the nephrotoxicity of oxalic acid is well recognized, the pathogenetic role of oxalate crystals in ethylene glycol intoxication has been questioned [248,255,263]. Instead, it has been suggested that interstitial edema with an impairment of intra-renal blood flow is the primary lesion to which the oxalate crystals are only coincidental. According to Levy, oxalate is secreted by the proximal convoluted tubules and chelates essential intracellular divalent cations such as magnesium and calcium, leading to cell necrosis [270]. In addition, experimental studies have suggested that cellular fragments can serve as heterogenous loci for the enucleation of calcium oxalate crystals [271]. Regardless of the merits of these particular points, several observations suggest that the effects of oxalate crystals may be less damaging than the cytotoxic effects of other ethylene glycol metabolites [248,255,265]. Monkeys poisoned with small ethylene glycol doses manifest tubular damage and deteriorating renal function in the absence of calcium oxalate crystals

Fig. 8. Ethylene glycol associated nephrotoxicity. Left panel: Intratubular polarizable crystals (hematoxylin and eosin, 100 x polarized). Right panel: Dengenerated tubules in association with oxalate crystals (hematoxylin and eosin, 200 x).

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[272]. Serial renal biopsies in patients reveal healing in the presence of crystals [273]. Glycoaldehyde, glycolic acid and glyoxylic acid produce only minimal to moderate renal oxalosis in rats, yet cause significant tubular damage, suggesting that the renal failure is at least partially due to the direct toxic effects of these compounds [248]. In summary, the accumulation of calcium oxalate crystals in the tubular lumen suggests an indirect, mechanical mechanism of ethylene glycol nephrotoxicity, but the importance of such other metabolites of relatively high polarity as glycolaldehyde, glycolic acid and glyoxylic acid which are cleared by the kidney must now also be recognized. 10. D-Penicillamine

D-Penicillamine was first isolated as the amine from the degradation products of penicillin [247]. Unlike its precursor, penicillamine lacks antibiotic activity, and so initial interest centered purely on its role in drug metabolism [275]. Penicillamine was first used pharmacologically to treat Wilson's disease [276]. Since, this agent has been used or proposed for use in cystinuria, rheumatoid arthritis, juvenile rheumatoid arthritis, palindromic rheumatism, scleroderma, primary biliary cirrhosis, alcohol detoxification, heavy metal removal, chronic active hepatitis, morphea, keloid, keratosis follicularis and hyperviscosity syndrome. In addition, it has been used in the preparation of radiopharmaceuticals for liver and kidney imaging [277]. A multitude of adverse effects of penicillamine have been reported including skin eruptions (quarter to half of patients), taste abnormalities (up to a quarter of patients), gastrointestinal toxicity (up to a third of patients), hepatic dysfunction, hematologic adverse effects and autoimmune syndromes [278]. The first example of penicillamine induced nephrotoxicity in the form of proteinuria was reported a few years after its introduction as a drug [279]. This adverse effect has since been observed in patients with a variety of conditions including rheumatoid arthritis, cystinuria and Wilson's disease [280-282]. Gastrointestinal absorption of penicillamine is rapid, but depends on the amount and type of food present. Antacids may decrease absorption by a third, iron administration by two-thirds. As much as a third of ingested drug may be degraded in the bowel before absorption. Peak plasma concentration occurs 1.5-3 h after ingestion. About 80% of D-penicillamine in blood is protein bound, mostly to albumin; 7% occurs as L-cysteine-D-penicillamine disulfide; 6% as free penicillamine; 5% as penicillamine disulfide and 2% is unaccounted for. Plasma clearance is biphasic; a first elimination phase with a half-life of about 1 h is followed by a much slower second elimination phase with a half-life of about 8 days. Usually a third of the ingested drug is eliminated in urine and half of that again in the feces [283]. Urinary excretion is mostly in the form of L-cysteine-o-penicillamine disulfide, although some free D-penicillamine and S-methyl-D-penicillamine are also detected. The risk of proteinuria, accompanied in the majority of cases by microscopic hematuria [284], has been found to increase at higher penicillamine doses by some [284,285], while others have found it unrelated to dose [286]. Genetic factors

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appear to influence the development, degree, and time of onset of peniciUamineinduced proteinuria. Risk is increased in patients who possess the HLA antigens B8 or DR3 [287,290], much as in those with prior gold-induced proteinuria [289-291], suggesting an idiosyncratic mechanism. Typically, proteinuria develops in the first 6-9 months of penicillamine therapy [290,292], but onset may be delayed up to the 25th month of therapy [278]. Proteinuria may be persistent, may be gradually progressive or may even present initially as an acute nephrotic syndrome [278]. If therapy is continued in patients with significant proteinuria (1-2 g/day), a third may proceed to nephrotic syndrome [292]. If penicillamine is discontinued, proteinuria usually falls to less than 2 g/day over 2-3 months. By 12 months after the discontinuation of therapy, proteinuria decreases to trace amounts [293]. However persistent proteinuria has been observed for over 2 years [286,293]. Individual cases of progressive proliferative glomerulonephritis [293-295], Goodpasture syndrome [296,297], renal vasculitis [298] and lupus nephritis [299-301], occur and may require intensive immunosuppression or even plasma exchange, but penicillamine nephropathy in general is reversible [302-303]. The typical histopathology is an immune complex membranous nephropathy similar to that seen in chrysotherapy as well [278,290,304]. Electron microscopy shows subepithelial electron-dense deposits and fusion of epithelial foot processes (Fig. 9). Immunofluorescence microscopy may demonstrate granular capillary wall deposits of IgG and C3 [281,304]. In penicillamine-induced Goodpasture syndrome, no differences from primary rheumatoid renal disease have been ascertained by light, immunofluorescent or electron microscopy [297]. After discontinuation of penicillamine, abnormal glomerular histology can persist for at least a year and typically lags the resolution of proteinuria [277,305]. While the electron-dense deposits are also known to disappear ('halos' in the membrane), complete reconstitution of the basement membrane has not been documented, since it would be against the medical principle of 'nil nocere' to re-biopsy a clinically resolved case. Rats fed penicillamine in high doses (2000 mg/kg) develop immune complex glomerulonephritis [306]. The mechanism by which the drug induces this process continues to be investigated. Based on experimental models, it has been suggested that equivalent amounts of antigen and antibody present in the circulation can combine to form soluble complexes which somehow become localized on the subepithelial side of the basement membrane. Alternatively, extravascular antigen-antibody complexes may form, in situ on the basement membrane [293]. Although in penicillamine nephropathy, immune complexes are demonstrable in the kidney, no evidence for circulating complexes exists [298,305], and serum C3 and C4 complement concentrations remain normal [284]. Together these facts suggest in situ complex formation. Precipitating antibodies to an ubiquitous antigen associated with nephritis may also play a role in both penicillamine and gold nephropathy [307]. Finally, elevated circulating antigalactosyl antibodies were seen in rheumatoid arthritis patients who developed proteinuria after treatment with penicillamine and gold, but the importance of this finding remains undetermined [308]. In summary, penicillamine causes significant proteinuria and morphologically a typical membranous nephropathy in up to a third of patients after a 6 months of

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Fig. 9. Penicillamine associated membranous glomerulonephritis exhibiting podocyte foot process fusion and rare scattered subepithelial electron dense deposits (arrows, transmission electron micrograph, 15 000 × ).

treatment. The idiosyncratic etiology is related to HLA genotype B-8 and DR3 as well as to the occurrence of prior proteinuria with gold therapy. If penicillamine is discontinued, the proteinuria resolves within a year in most cases, but there are reported cases of renal insufficiency and of more severe histopathological presentations. Resolution of the structural changes lags behind the disappearance of proteinuria. 11. Methicillin

Methicillin (dimethoxyphenyl penicillin) is a semi-synthetic penicillin, and the first penicillin resistant to penicillinase. When it became available in 1960, this drug represented a major advance in antistaphylococcal therapy. Since it is acid labile, methicillin can not be administered orally. After an intramuscular dose, it has a plasma half-life of 30 min, is actively secreted by the renal tubules, and 70-80% appears in the urine. Minimal inhibitory and bactericidal concentrations are easily achieved without incurring dose-related toxicity [309].

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As early as 1961, three methicillin-related cases of fever, eosinophilia, albuminuria, hematuria and azotemia were reported [310]. These symptoms resolved with the discontinuation of methiciUin therapy, and renal function returned to baseline. A review of 12 cases reported in 1968 that hematuria and proteinuria were present in all, starting 7-30 days after initiation of therapy [311]. Spiking fever unrelated to the primary infectious process was present in ten of the cases and responded to discontinuation of therapy; five cases had a rash, and nine, eosinophilia. In one case the fever and hematuria recurred 'immediately' after methicillin was reinstituted and ceased when again discontinued. This presentation suggested a hypersensitivity reaction, which in subsequent investigations appeared related to neither the dose nor the duration of therapy. At about the time this infrequent clinical intolerance was established, the morphology of the renal lesion was described as an acute interstitial nephritis [312-314]. The characteristic methicillin lesion consists of a linear accumulation of small and medium lymphocytes located closely adjacent to the outer tubular profile, and of other lymphocytes on the opposite side of the tubular basement membrane insinuated within the epithelium between adjacent tubular cells. The lumens of affected tubules usually contain both sloughed, degenerated epithelial cells and inflammatory cells. Clusters of eosinophils are commonly seen in the edematous renal interstitium, surrounding and infiltrating the tubules. In one case, eosinophils were aggregated focally into micro abscesses. These findings explain the eosinophiluria reported in every case [315]. Plasma cells and an occasional neutrophil also may occur in the inflammatory infiltrate [316]. The clinical correlate of these changes are various degrees of renal impairment and azotemia. Generally most adults have spontaneous remission or respond well to prednisone, but methicillin has also been reported to cause permanent renal damage [317,318]. In these latter cases, evidence of a causal relationship, is not unequivocally convincing. However, damage from methicillin nephrotoxicity is certainly cumulative in repeated exposure. In children the nephrotoxic lesion appears less severe [314,315]. Considerable evidence suggests that the renal lesions of methicillin result from an immunological rather than a toxic mechanism. Only few patients exposed to the drug develop interstitial nephritis, and this is not dose related. Moreover, most cases evidence hypersensitivity with fever, rash, arthralgia and eosinophilia. Repeated exposure to the same or to a closely-related drug may precipitate recurrence [313,318]. However, the possibility must be ruled-out that the infection, say scarlet fever or diphtheria, originally necessitating treatment caused the interstitial nephritis. As it is, the typical renal lesions have developed in patients treated for a multiplicity of infections known not to involve the kidneys. Moreover, severe interstitial nephritis has occurred in patients given methicillin prophylactically [319]. The immunological mechanisms of methicillin induced interstitial nephritis remain obscure. Early on IgG and IgM antibodies to benzyl penicilloyl antigen were demonstrated in serum. Immunofluorescent antibody studies localized dimethoxyphenyl penicilloyl hapten in the region of glomerular and tubular basement membranes [312]. Antitubular basement-membrane antibodies directed to-

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ward a dimethoxyphenylpenicilloyl hapten have been reported in two cases [320,321]. Linear accumulations of IgG and C3, together with a methicillin-derived antigen have been found along tubular basement membranes [322-324]. It has been suggested that dimethoxyphenyl penicillin, which is largely secreted by the proximal tubules, binds to the tubular basement membrane and causes the formation of a methicillin-tubular basement membrane conjugate that stimulates antitubular basement-membrane antibody production. Two hypotheses may explain these observations: (a) methicillin may bind to renal tissue in all subjects and the subsequent development of lesions depends on an unusual immune response, whether humoral or cell mediated; or (b) the binding of hapten may only occur in patients who develop interstitial nephritis. Experiments to establish the correct alternative continue to be inconclusive [318]. One study of nine cases of drug-induced interstitial nephritis only found antitubular basement membrane antibodies in two cases [325]. Immunofluorescence assays of five renal biopsies in the same series showed the following patterns: linear deposits of IgG (one biopsy) and C3 (two biopsies) along tubular basement membranes, IgG bearing cells in the interstitium (one biopsy) and patchy interstitial deposits of fibrinogen and IgG (one biopsy). IgE concentrations were elevated in three of seven available serum specimens. These aggregate findings were thought to suggest a heterogenous pathogenetic mechanism. It is also conceivable that anti-tubular basement membrane antibodies develop secondary to toxic tubular damage as the primary event [318]. However, the overwhelming evidence points toward a primary hypersensitivity, whose exact type continues to be debated. A type II (cytotoxic) mechanism is commonly postulated as a Goodpasture's type reaction to tubular basement membrane [312,320,321]. This cannot be well distinguished from a type III (immune complex disease) process to the same antigen hapten [312,320,321]. A weak argument for a humoral immune mechanism is the reduction of serum complement observed in methicillin nephrotoxicity [325]. Type I (anaphylactic) hypersensitivity is suggested by increased IgE levels [316,322]. Finally, some who detected no antibodies [326] or observed positive lymphocyte transformation [327] in methicillin interstitial nephritis have postulated a type IV (cell mediated) mechanism. However, no direct evidence for T cell participation exists. In summary, methicillin infrequently causes acute interstitial nephritis. This adverse effect is believed to be due to hypersensitivity rather than toxicity, but the immunological mechanism remains obscure.

Acknowledgement The authors thank Dr. Andrew Abraham for advice and illustrative material.

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