Mechanisms in the development of analgesic nephropathy

Kidney International, Vol. /8 (/980), pp. 553 —561

Mechanisms in the development of analgesic nephropathy GEOFFREY G. DUGGIN Renal Unit, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia

Olfsson, Gudmundsson, and Brekkan [6] studied 49

Analgesic nephropathy is a unique drug-induced kidney disease. It is characterized by renal papillary necrosis and interstitial nephritis resulting from prolonged excessive consumption of combination antipyretic analgesics. Antipyretic analgesics have been used in clinical medicine since the late nineteenth century. Buss in-

unselected patients with nonobstructive pyelonephritis without diabetes mellitus or stones and found

38% abused analgesics. Data from the Australian and New Zealand Dialysis and Transplant Registry [7] also showed that patients who abused combination analgesics developed renal disease, and approximately 20% of patients on the Australian program for dialysis and transplant were there as a re-

troduced sodium salicylate in 1895, Dresser introduced aspirin in 1897, phenacetin in 1887, and

sult of analgesic-induced kidney disease. The

Von Merring introduced paracetamol (acetaminophen) in 1893 [1]. These drugs have found widespread use as everyday remedies in almost every country in the world. It was not until 1953, however, that Spuehier and Zollinger [2] described the renal disease associated with the chronic consumption of combination analgesics containing phenace-

correlation between the severity of renal disease and the extent of analgesic abuse had been demon-

strated by Gault, Blennerhassett, and Muehrcke [8], who found a linearly increased relationship between the amount of analgesic consumed and the severity of renal disease, as assessed by creatinine

tin.

clearance and renal biopsy. Nordenfelt [9] also

There is now overwhelming evidence that consumption of combination analgesics is causally associated with renal disease. Clinical and epidemiologic studies indicate an increased incidence of re-

showed that the decreased availability of phenacetin-containing compound analgesics in Sweden had led to a marked decline in the incidence of kidney disease in that country. The incidence of patients

nal disease in people who abuse analgesics.

with analgesic nephropathy per country also remarkably parallels the per capita consumption of phenacetin in that country [5]. In 1967, Australia

Nordenfelt and Ringertz [3] found that 29% of people who had consumed an estimated kilogram or greater of phenacetin in a combination analgesic had evidence of renal damage. Larsen and Moller [4] found that 33% of people with a similar intake had reduced renal function, as evidenced by a decrease in creatinine clearance, compared with only

had a per capita consumption of phenacetin of 40 g per year, and the highest incidence of analgesic nephropathy. This was followed by Scandinavia with 25 g; Switzerland with 22 g and South Africa and

Scotland with 12 g per year. In Canada and the USA, the disease is relatively uncommon, and the per capita consumption was 7 g and 10 g, respectively. Further evidence implicating analgesics was provided by two studies that examined the cessation of analgesic consumption by patients who had abused them. Linton [10] showed that patients who ceased analgesic consumption either maintained or

7% in a matched control group. Others have report-

ed the incidence of renal impairment to vary between 3 and 90%, being greater in each instance than in the normal population with which they were compared. The apparent discrepancies result from the different methods used to determine renal func-

tion, the amount of drugs consumed, and the different combinations of analgesics. The incidence of analgesic abuse in patients with renal disease further supports a causal relationship. Murray and Goldberg [5] reported that 20% of patients with chronic interstitial nephritis abused analgesics.

Received for publication May 29, 1980 0085—2538/80/0018-0553 $01.80

© 1980 by the International Society of Nephrology

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improved renal function, whereas those who continued to consume analgesics had a further deterioration. A similar study in Australia [11] showed comparable results. Until 1964, it was widely accepted that phenacetin was the agent primarily responsible for the disease. This was largely based on clinical data from Western Europe, particularly Switzerland and Sweden. Gilman, in an editorial [12], questioned the validity of the theory that phenacetin caused the disease. This resulted in considerable controversy as to which drug was responsible for the disease. Nan-

ease who were treated over a 2-year period with high dose salicylates and who had no change in renal function. Until recently, most investigators have concentrated on a single drug being responsible for the disease. As there is a striking association between the abuse of combination analgesics and the disease, this raises the possibility of synergistic toxicity with the combination of these drugs [14]. Clinical evidence to support this contention is provided by Ferguson et al. [16], who studied patients attending a clinic for rheumatism. Patients who had consumed

ra et al [13] found that aspirin in doses of 500 mg/kg/

in excess of 1 kg of aspirin alone had a 0.3% in-

day or phenacetin or paracetamol in doses of 3000 mg/kg/day resulted in a disease in rats similar to the analgesic-induced disease in man. They suggested

cidence of papillary necrosis, whereas patients who had consumed in excess of 1 kg of combination analgesics containing aspirin and phenacetin or para-

that aspirin was more likely to be the principal agent. The doses used in their animals, however, bore no relationship to those consumed by man, as

they exceeded the expected lethal dose. Also, as several drugs produce the disease, species differences in drug metabolism and pharmacokinetics may change the dose relationship in man [14]. Nanra and Kincaid Smith [15] also provided further evidence from a pathology study of patients who had rheumatoid arthritis, treated with high dose salicylates. it was found that 59% of autopsy specimens had evidence of papillary necrosis. But this study was retrospective, and no data are available regarding the abuse of combination analgesics—important

cetamol had a 10.6% incidence of the disease. A

prospective study by Dubach et a! [22] in Switzerland provided evidence that combination analgesics containing phenacetin produced evidence of renal disease. The study involved 623 people employed in watch factories in Switzerland. These subjects were found to have phenacetin metabolites (measured as paracetamol) present in their urine, and were com-

pared to an age-, sex-, and occupation-matched control group, who had no drug present. Over the 4year period of study, 3.8% of the phenacetin group developed an abnormal urine concentrating capac-

ity, against 0.8% of the control group. The in-

known to use nonmedically prescribed combination analgesics in addition to their medically prescribed medications [16]. Several studies question the primary role of aspirin. Leonards [17] was unable to produce analgesic nephropathy in 200 rats treated with 500 mg/kg/day of aspirin over a 6-month period. Phillips et al [18] used doses more closely approaching those of human consumption (24 to 126 mg/kg/day) and found no evidence that aspirin alone could induce renal

cidence of raised serum creatinine was 2.9% in the phenacetin group and 0.4% in the control group. The data were even more significant when the phenacetin group was subdivided into those showing evidence of high and low consumption: 5.4% of the high consumption group and 0.4% of the low consumption group had raised serum creatinine levels. These relatively small percentages are more important when one considers that plasma creatinine does not become elevated above the normal range until almost 50% of renal function is lost; also, that in papillary necrosis, extensive disease with consid-

disease. Studies of pigs [19] given aspirin for 6

erable scarring is present before any significant

months produced no evidence of papillary necrosis. Several clinical studies also refuted the role of aspirin as a sole drug. The New Zealand Rheumatism Association study [20] of 1081 patients with rheumatic diseases treated with salicylates showed that

change occurs in creatinine clearance [23]. Recently, the pathology of the disease has been reviewed extensively [24, 25]. Lindeneg et a! [26] suggested that the disease commenced in the renal papillae and resulted in necrosis of this anatomically discrete tissue. This then may lead to secondary

in this group of patients who, in Australia, are

the only patients with evidence of renal disease were a small group who had abused aspirinlphenacetin or aspirinlparacetamol combinations. This was also supported by a prospective study in Newcastle-on-Tyne [21] of patients with rheumatic dis-

nephron damage. Gault, Blennerhassett, and Muehrcke [8], in a study of patients with analgesic nephropathy, using percutaneous renal biopsy, confirmed and extended these findings; the initial lesion

Analgesic nephropathy

555

is necrosis, particularly of interstitial cells, and

goes metabolism to produce tissue necrosis—a

some sclerosis of the renal papillae. As the quantity of analgesic consumed increases, there is complete necrosis of the renal medulla; this is then followed by nephron death and cortical interstitial nephritis,

great deal of data have been accumulated.

often associated with separation of the renal papillae or portions thereof.

In Australia, it has been demonstrated that the presentation of patients to a hospital is more common in summer than it is winter and that the disease has acute exacerbations during episodes of dehydration [27]. One of the major contributing factors to this phenomenon is the high concentration of the drug in the papilla during these episodes, leading to selective tissue damage. Hypotheses for pathophysiologic mechanism

For a drug to induce selective damage to the renal papillae, the drug or its derivative must satisfy one or both of the following criteria: (1) The tissue must have unique metabolic or functional features that render it sensitive to the drug. (2) The drug must be concentrated selectively within that tissue. With regard to the first hypothesis, several work-

ers have suggested that the principal event is ischemic necrosis of the papillae, because of the nature of the blood supply to this tissue. Molland [28] demonstrated changes within the vasa recta epithe-

hum and postulated a decreased papillary blood flow leading to ischemic necrosis. Nanra, Chirawong, and Kincaid Smith [29] have demonstrated in rats given 500 mg/kg of aspirin a decreased medullary blood volume, as determined by the fluorescent tanned red cell method. Their data do not, however,

show decreased blood flow to the papilla, as the method used determines blood volume and not blood flow, and the tissue swelling associated with

papillary necrosis may alone be sufficient to account for the decreased blood volume within the tissue. They have postulated that there may be inhibition of renomedullary prostaglandins. Caterson and Duggin [30] demonstrated that small doses of aspirin noncompetitively inhibit prostaglandin synthetase in the kidney, both in the renal cortex and the renal medulla. If this were the mechanism, people consuming small doses of aspirin daily might be expected to develop the disease, but this has not been demonstrated. With respect to the second hypothesis—that the

Renal excretory mechanisms of analgesics

Phenacetin. Metabolic studies indicate that this compound undergoes extensive first-pass metabolism in the liver to paracetamol, so that only when large doses are consumed do even small concentrations appear in the peripheral circulation [31]. Phenacetin is only weakly protein bound to plasma pro-

teins [32], undergoes glomerular filtration, and is passively reabsorbed by the tubule [32]. The drug is

very lipid soluble, and at all urine flow rates the urine-to-plasma ratio (U/P ratio) remains in unity. This indicates a diffusion rate from the tubular lumen equal to that of water. The phenacetinlinulin clearance ratio rises linearly with the urine flow rate. The plasma concentration of phenacetin and the urine pH have no influence on the clearance of phenacetin by the kidney. A stop-flow study [32] indicated no specific site of reabsorption of phenace-

tin along the tubule, the urine-to-plasma ratio in both proximal and distal regions being in unity. Paracetamol (acetaminophen). Barraclough [33] showed that the U/P ratio of paracetamol increased in response to vasopressin. Prescott and Wright [34]

demonstrated in man that paracetamol clearance was increased by increased urine flow rate and not influenced by urine pH. They also showed that excretion of the major conjugates of paracetamol was not affected by urine flow. Duggin and Mudge [35] examined the mechanisms of tubular transport in dogs, and found close agreement with the findings of Prescott and Wright. In the dog, paracetamol is only approximately 13% protein bound, and hence undergoes glomerular filtration. Clearance increases with an increase in urine flow rate in a curvilinear manner, somewhat similar to urea. The fractional excretion of paracetamol is 0.26 when the fractional

excretion of water is 0.05; this increases to 0.40 when the fractional excretion of water rises to 0.12. The clearance is independent of the plasma concentration of the drug, and urine pH has no effect. Sil-

berbush et a! [36] studied paracetamol clearance during paracetamol loading and following loading. They also found renal accumulation of paracetamol.

Their clearance data are in close agreement with those of Duggin and Mudge, as are also the findings of Ross et al [37], who studied the renal clearance of paracetamol in the isolated perfused rat kidney.

drug becomes concentrated within the tissue as a

The conjugates of paracetamol have quite dif-

result of the renal excretory mechanism, and under-

ferent mechanisms of transport. At low plasma con-

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Duggin

centrations, both the sulphate and glucuronide conjugates undergo net tubular secretion. At high plasma concentrations, net tubular secretion decreases

and net tubular reabsorption becomes apparent. Tubular secretion at low plasma concentrations is inhibited by probenecid. These data suggest that the conjugates of paracetamol undergo bidirectional active transport within the proximal tubule. Stop-flow

studies [35] demonstrated that for paracetamol there was no specific site of reabsorption and the rate of diffusion was less than that of water. The conjugates of paracetamol had a proximal site of reabsorption, and this was inhibited by probenecid.

Aspirin. Although the renal excretory mechanisms of salicylate have been investigated extensively since the 1940's, (see below), those of aspirin have not. The reason has been the lability of aspirin in biologic fluids [30]. Recent methods of analysis,

especially high-pressure liquid chromatography [39], have overcome many of these problems. Studies in the rabbit (Caterson and Duggin, unpublished) are complicated by the rapid in vivo conversion of

aspirin to salicylate. This introduces at least three problems in the measurement and interpretation of renal clearance: First, the tubular transport of aspirin must always be measured in the presence of var-

iable concentrations of another organic anion, for example, salicylate, which acts as a competitor for active transport. Second, the extent of the reversible binding of aspirin to plasma protein can only be

measured with an error of unknown degree, because aspirin undergoes a rapid transacetylation reaction with protein which yields acetylated protein and salicylate as products [30, 40]. It is not known whether the binding of aspirin is the same for acetylated as for nonacetylated proteins. Third, aspirin acetylates kidney protein directly. Except at very low doses, this process is dose-dependent and is unsaturatable at high single doses of aspirin [30]. It is not known to what extent reactions of this type distort the usual estimates of tubular transport that are

made in the conventional manner on the basis of clearance data. Despite the above limitations, aspirin appears to behave in a manner qualitatively similar to that of salicylate. At low plasma concentrations, there is net tubular secretion that is probenecid-sensitive; at

high plasma concentrations, there is net tubular reabsorption. These data suggest bidirectional active transport in the proximal tubule. In addition, aspirin excretion is increased by alkalinization of the urine or an increase in the rate of urine flow.

These findings suggest that reabsorptive transport also occurs by nonionic diffusion. Saucy/ate. Studies in several species, including man, identify at least three components in the renal disposition of salicylate: filtration (of that fraction that is not bound to plasma protein), active secretory transport in the proximal tubule, and nonionic diffusive reabsorption throughout most of the nephron [38, 41, 42]. It has been suggested that in addition to nonionic diffusion, a specifically mediated reabsorptive mechanism for salicylate exists in the proximal tubule [42]. The importance of nonionic diffusion as a determinant of salicylate excretion is indicated by the fact that clearance may range from virtually zero at low urinary pH to values exceeding the filtration rate at high urinary pH. As expected,

clearance is positively correlated with urine flow rate. Under stable physiologic conditions, clearance diminishes as plasma concentration of salicylate increases. This phenomenon is thought to be a consequence of saturating the secretory mechanism [41].

Intrarenal distribution of analgesics

A limited number of drugs have been studied with respect to their distribution in the kidney. Most reports have been confined to the concentration within the total tissue, and most authors have not determined any compartmental distribution within the kidney. This is particularly important in the kidney, as this organ has an intratubular compartment in addition to the usual intracellular and interstitial compartments. Hence, it is possible for two compounds to have equal total tissue concentrations, one compound being distributed evenly throughout all compartments and the second being concentrated only within a singular compartment. This is particularly important when considering drug toxicity, because

it is probable that the mechanism of toxicity in-

volves an intracellular site of action. A summary of the available data is given in Table 1. Phenacetin. Barraclough and Nilan [43] reported that the tubular transport of phenacetin was influenced by vasopressin and that under conditions of antidiuresis there was an increased concentration of

phenacetin in the medulla, relative to the cortex. Their method [44] of determining phenacetin, how-

ever, has been shown to be unsuitable for urinary and kidney tissue samples, as the method simultaneously determines both phenacetin and a metabolite [45]. In a study [45] using a specific high-performance liquid chromatography method for deter-

557

Analgesic nephropathy Table 1. Intrarenal distributiona

Intracellular distribution

Concentration Drug

Phenacetin (dog) Paracetamol (dog) Paracetamol conjugates (dog) Salicylate (rabbit) Inulin (dog)

Plasma

Cortex

Papilla

Urine

inpapilla +

1

1

1

1.5

4

16

+

1

5

6

13

95 90

+

8

100

0

1 1 1 1 1

1.5

0

Data is from literature for antidiuresis [32, 35, 511 (Caterson and Duggin, unpublished). Plasma concentrations were normalized to unity; for purposes of summary, a single value was obtained by inspection of available graphs.

mining phenacetin [46], it was demonstrated that both under conditions of diuresis and antidiuresis, no corticopapillary concentration gradient developed. Further analysis of these data has indicated that phenacetin is distributed uniformly in the intratubular, intracellular, and interstitial compartments of both the cortex and medulla (Table 1). Paracetamol. There are only two studies on the

renal distribution of paracetamol. Bluemle and Goldberg [47], in a study in dogs, examined the renal cortical, corticomedullary junction, and medullary concentrations of paracetamol, following the administration of phenacetin. Their data indicated that during antidiuresis there was a significant corticopapillary concentration gradient, and that during diuresis, no gradient developed. The gradient was similar to that developed for the polar conjugates of paracetamol. They concluded that paracetamol and its conjugates were transported in a manner similar to urea and underwent countercurrent multiplication. The possibility was not considered, however, that the compounds might exist at different concentrations in different compartments within the me-

dulla. In the distal nephron within the renal medulla, one would expect the highly polar conjugates of paracetamol to be confined to the tubular lumen. The concentration would be high within this compartment because of the proximal tubular secretion

medulla was on the average 2.3 times larger than that of inulin during both antidiuresis and diuresis. Thus, because inulin is confined to the intratubular and interstitial compartments, paracetamol must be distributed within the cells of the medulla. The medullary concentration reached as high as seven times

the cortical concentration during antidiuresis, but this gradient was absent in diuresis. Aspirin. There have been no published studies on the intrarenal distribution of aspirin. Caterson and Duggin (unpublished) have studied this in rabbits. The mean renal cortical concentration was one half that of the plasma. During diuresis there was a small

corticopapillary concentration gradient, 1.0:1.2, which increased to 1.0:4.5 during antidiuresis (U/P inulin, between 60 and 160). The volume of distribution in the medulla was greater than that of inulin, indicating an intracellular distribution, and this volume was increased in animals with an acid urine. In

the rabbit, urine pH did not fall below 6.7; a far lower minimal pH would be anticipated in man. It is possible, therefore, that with maximal acidification the volume of distribution of aspirin within the papilla would be greater in man than in the rabbit. Salicylate. Despite the large number of studies on

the renal excretion and renal tubular transport of salicylate, there have been but few studies on its renal concentration and intrarenal distribution.

along the length of the tubule. The moderately polar parent drug, paracetamol, might be expected to diffuse into the cells and interstitial fluid. Duggin and Mudge [48] tested this hypothesis in a study in dogs, using inulin as a marker because it is an inert non-

Quintanilla and Kessler [49] studied the renal clearance in dogs and also performed a limited number of investigations on the renal cortical and medullary concentrations. They found a concentration in the cortex of 0.5 times the plasma, and the medullary concentration to be the same as the plasma concen-

reabsorbable compound. Concentrations in the

tration, making a corticopapillary concentration

urine were used for reference in the calculation of the volume of distribution within the medulla. The volume of distribution for the conjugates of paracetamol in the medulla was similar to that of inulin, but the volume of distribution of paracetamol in the

gradient of 1:2. Bluemle and Goldberg [47] studied

of these conjugates and the reabsorption of water

the renal cortical, corticomedullary junction, and medullary concentration of salicylate during diuresis and antidiuresis. Their data may be questioned, however, because of the analytic method used [50].

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Duggin

This is suitable for determining the salicylate concentration in plasma, but unsuitable for determining urine or tissue concentrations, because of the presence of interfering metabolites. Caterson and Duggin [51] studied rabbits following the i.v. adminis-

mediate was originally postulated to be N-OH para-

tration of salicylate or aspirin. Using a specific highperformance liquid chromatography method for de-

medulla, the concentration was 3.4 times the

dosage [59]. Mudge, Gemborys, and Duggin [60] and McMurtry, Snodgrass, and Mitchell [61] have demonstrated that a similar mechanism of metabolic activation and glutathione depletion exists within the kidney. The mechanism of acute renal failure following paracetamol overdosage does not, how-

plasma. The resultant corticomedullary gradient

ever, mimic the disease state of analgesic nephropa-

termining salicylate [39], they showed that during diuresis the mean salicylate concentration in the cortex was 1.8 times that of the plasma; in the renal was 1.0:1.9. During antidiuresis, the mean concentration in the cortex was 6 times that in the plasma, and in the medulla was 13.2 times, giving a corticomedullary concentration ratio of 1.0:2.2. They also compared the intrarenal distribution of salicylate with that of inulin. Salicylate was distributed within the tubules and the cells of the medulla. The volume of distribution increased with an acid urine and was decreased with an alkaline urine. As with aspi-

rin, this pH dependence might be expected to be particularly important in man in whom the urine is

normally acid, particularly during antidiuresis. Beyer and Gelanden [52] studied the concentration of salicylate in the dog and found a corticopapillary concentration ratio of 1.5 to 2.0 during diuresis and 2.0 to 3.0 during antidiuresis. Although they did not study the intrarenal distribution further, their data would support that of Caterson and Duggin [51]. Metabolism of analgesics within the kidney

cetamol [56], but recent evidence by this group casts some doubt on this hypothesis [58]. There are now numerous reports of acute renal

failure in patients following paracetamol over-

thy, where the principal lesion occurs in the renal papilla and medulla, and not in the renal cortex, and there has not, to date, been reported hepatic damage in patients with analgesic nephropathy. Thus, the mechanism for analgesic nephropathy must be

somewhat different than that of the acute overdosage situation. Paracetamol, aspirin, and saucylate during antidiuresis achieve higher concentrations in the renal medulla than they do in the renal cortex or other tissues. The concentration of paracetamol in the medulla may be five to seven times higher than is that in the renal cortex. In this situation, the concentration of the drug in the medulla after a large therapeutic dose will be equivalent to the concentration in the liver following an overdosage of the drug. Paracetamol undergoes metabolic activation to a reactive intermediate in the renal cortex [60, 61] and the renal medulla [62]. In the renal cortex, this ap-

depleted by conjugation to paracetamol, leaving the

pears to be mediated by a microsomal cytochrome P450-dependent monoxygenase (as in the liver). In the papilla, there is only a minimal concentration of cytochrome P450 (Duggin and Mohandas, unpublished). Electron microscopy indicates that there are only small numbers of microsomes or rough endoplasmic reticulum (Duggin and Ham, unpublished). Ross et al [37] (this issue) have demonstrated that paracetamol is metabolized in the isolated perfused kidney and that metabolites derived from glutathione conjugates are excreted. Mohandas et al [62, 63] have compared the metabolism of paracetamol in the kidney of the rabbit to that of the C57BL/6J mouse. In the rabbit cortex and whole kidney of C57BLI6J mouse, metabolic activity and subsequent covalent binding are largely dependent on NADPH, whereas in the medulla of the rabbit, this system shows only a small degree of

cell unprotected against electrophilic attack, and the reactive intermediate then covalently combines with cellular proteins. The end result of this series of reactions is cellular necrosis. The reactive inter-

however, a totally different system, which leads to covalent binding of the drug to tissue protein. This system is independent of NADPH, is inhibited by

The activation by metabolism of a variety of xenobiotics to toxic chemicals has been well described in the liver [53]. There are only a limited number of studies on metabolic activation of drugs within the kidney (for review see Anders, this issue [541).

It has been observed that patients consuming massive doses of paracetamol (as an overdosage with suicidal intent) will have, as a result, acute hepatic necrosis [55]. The mechanisms for this have been studied by Jollow et al [56] and Mitchell et al [57], who have demonstrated that paracetamol undergoes metabolic activation to a chemically reactive intermediate, which conjugates with the tripeptide glutathione. In the massive overdosage situa-

tion, however, the cellular glutathione becomes

activity. In the medulla of rabbits, there exists,

Analgesic nephroparhy

fluoride (which stimulates binding in the NADPH dependent system), and is inhibited by acetyl Co-A and p-aminophenol. Thus, covalent binding to proteins in the renal medulla is by a mechanism different from that which occurs in the renal cortex and liver. Covalent binding during antidiuresis occurs to a greater extent in the medulla than it does in the cortex [60]. The half life of the paracetamol covalently bound to protein in the medulla is in the order of 120 hours. Glutathione depletion in the kidney also occurs as a result of paracetamol administration [60, 61]. The extent to which this occurs is not as great as that of the liver. The kidney cells are thought, however, to have at least two poois of glutathione [64]; one is confined to the cell membrane, the other is intracellular. It is not known whether these pools are affected differently by a reactive metabolite of the drug. Phenacetin may not play a direct role in papillary necrosis for two reasons. First, as a result of hepatic metabolism [31], systemic, as well as urinary, concentrations of phenacetin are extremely low. Second, phenacetin itself does not become concen-

559

gin and Mudge, unpublished). The mechanism appears to be related to the high concentration of salicylate achieved in the kidney, compared with the liver [51]. The biochemical mechanism for this phenomenon has not been definitely elucidated. It does not appear to be as a result of salicylate conjugation to the glutathione, as there have been no mercapturic acid metabolites of salicylate reported, and the

administration of labeled salicylate and labeled glutathione does not result in the appearance of doubly labeled conjugate (Caterson and Duggin, un-

published). Goldberg et a! [68] demonstrated that salicylate in high concentration in vitro inhibits the pentose phosphate shunt, which is largely responsible for maintaining reduced glutathione. With in vivo confirmation, this may ultimately prove to be the mechanism. Summary. Clinical and epidemiologic evidence indicates that analgesic nephropathy results from the excessive consumption of combination analge-

sics, especially those containing paracetamol (acetaminophen) or its analog, phenacetin. The most common analgesic combination currently producing the disease in Australia contains aspirin and

trated within the medulla [32]. From the hepatic me-

paracetamol. To elucidate the mechanism of the

tabolism of phenacetin, paracetamol is formed as the major metabolite. According to the present evidence, this metabolic route accounts for the ultimate nephrotoxicity that may result from the ingestion of phenacetin. A minor metabolite of phenacetin (N-hydroxy phenacetin) is a relatively stable

disease, a systematic series of studies have been un-

compound and is unlikely to act as the primary arylating compound [65]. Aspirin has been demonstrated to acetylate covalently serum albumin [40], hemoglobin [66], platelet particulate protein [67], and renal cortical and medullary proteins [30]. This acetylation of proteins is via a nonenzymatic transacetylation reaction and is

comes concentrated in the renal medulla during antidiuresis, achieving a concentration approxi-

presumably widespread in many tissues. The half life of the covalently bound acetyl residues is approximately 130 hours in the renal medulla. The only functional abnormality reported as a result of this

acetylation has been the remarkable inhibition of prostaglandin synthetase (cyclooxygenase) in the platelet [68] and the renal cortex and medulla [30]. It is conceivable, however, that other enzyme systems may be affected, but they are unlikely to be of major importance in the development of papillary necrosis when aspirin is consumed alone. Salicylate has been demonstrated to produce a very significant reduction of renal glutathione when

administered to experimental animals, without a change in hepatic glutathione concentration (Dug-

dertaken to examine the renal excretory mechanisms, intrarenal concentration and distribution, and renal metabolism of these drugs. Paracetamol undergoes glomerular filtration and is passively reabsorbed by the tubules. The drug bemately five to seven times that achieved in the renal

cortex or plasma. Phenacetin does not achieve a concentration in the medulla greater than that in the

renal cortex or the plasma. Aspirin and salicylate undergo proximal renal tubular secretion by the organic anion secretory system. Both are reabsorbed by the distal nephron by nonionic diffusion and be-

come concentrated in the medulla during antidiuresis. In the case of aspirin, paracetamol, and salicylate, all three, in addition to becoming concentrated in the medulla in antidiuresis, are distributed within the intracellular compartment of that region. Many of the biochemical events that could lead to papillary necrosis have been defined. Salicylate de-

pletes cellular glutathione in the kidney, but the mechanism producing this change is, as yet, unclear. Paracetamol becomes metabolized to a highly reactive intermediate by both a NADPH-dependent and a NADPH-independent mechanism, and this in-

termediate (or intermediates) subsequently cova-

560

Duggin 15. NANRA RS, KINCAID SMITH P: Analgesic induced renal dis-

lently binds to tissue proteins when glutathione concentrations are reduced. In addition, aspirin directly acetylates kidney proteins but the consequences of this reaction are not known as far as nephrotoxic-

16. FERGUSON 1, JOHNSON F, REAY B, WIGLEY R: Aspirin, phe-

ity is concerned. Thus, the combination of saucylate and paracetamol may be synergistic in increasing covalent binding. This process, if repeated dai-

17. LEONARDS JR: Does aspirin cause analgesic nephropathy in rats? inAbst 5th mt Cong Nephrol, edited by VILLAREAL H, Mexico City, Basel, New York, S. Kanger, p. 50, 1972

ly, could lead to sufficient covalent binding to produce cell death and the disease state of analgesic nephropathy. Acknowledgments

Several studies reported in this review have been supported by the National Health and Medical Research Council of Australia and the Australian Kid-

ney Foundation. Ms. Richmond assisted in preparing the manuscript. Reprint requests to Dr. G. G. Duggin, Renal Unit, Royal Prince Alfred Hospital, Camperdown, Sydney 2050, Australia

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