Letter: The clinical course of patients with analgesic nephropathy.

Thirty-four patients with analgesic nephropathy were followed at intervals of 1 to 3 months with measurements of creatinine clearance and serum concentration of acetylsalicylic acid (ASA) for a total of 105 patient-years. Diagnostic criteria included total consumption of at least 2 kg of phenacetin and 3 kg of ASA, compatible tissue abnormality on biopsy and evidence of papillary necrosis on an intravenous pyelogram. Nephropathy was induced by the same compound analgesic containing ASA, pehnacetin, caffeine and codeine (APC&C) in 30. Phenacetin was removed from this preparation in 1970 and replaced by an approximately equal amount of ASA (ACC). Creatinine clearance remained unchanged or improved in 11 of 15 patients who stopped taking analgesics containing phenacetin or ASA and in 10 of 11 of those who continued to take the ACC preparation. In contrast, renal function deteriorated in seven of eight patients who continued to abuse APC&C analgesics. The results suggest that phenacetin is necessary for the major nephrotoxic effect of this APC&C combination, but that ASA is not absolved of some nephrotoxicity.     

Analgesic Nephropathy: Removal of Phenacetin from Proprietary Analgesics

Since phenacetin was withdrawn from Askit Powders and Beecham''s Powders in 1966 these preparations have declined in importance as a cause of analgesic nephropathy in Western Scotland. In most patients with analgesic nephropathy who persist in abuse of compound analgesics renal function continues to decline. The deterioration, however, is less rapid among those taking aspirin and caffeine mixtures than in those taking preparations which also contain phenacetin.     

Declining incidence of analgesic nephropathy in Canada.

Surveys of nephrologists in Canada indicate that the incidence of analgesic nephropathy has decreased by about 50% in less than a decade in association with the removal of phenacetin from the market and restrictions on the availability analgesic mixtures containing acetaminophen and acetylsalicylic acid. The number of patients presenting with end-stage renal disease attributed to analgesics has shown a similar drop. These decreases have occurred in spite of increased consumption of acetaminophen as a single analgesic. Analgesic nephropathy should not be expected to disappear, however, since there is evidence that the drugs still in use have the potential to cause renal damage.     

Papillary Necrosis in Experimental Analgesic Nephropathy

A proprietary aspirin, phenacetin, and caffeine preparation given to rats in a dose equivalent to that taken by patients with analgesic nephropathy produced papillary necrosis in 55%. There was a higher incidence in rats deprived of fluids overnight.Papillary necrosis was not noted in rats receiving twice as much phenacetin.These findings support the argument that phenacetin should not be singled out as the substance responsible for analgesic nephropathy in man.     

Analgesic Nephropathy. Clinical Course after Withdrawal of Phenacetin

Of 14 patients with analgesic nephropathy 11 were followed up for 9 to 88 (mean 36) months after withdrawal of analgesics containing phenacetin. Ten of these 11 are still alive and have improving, static, or very slowly declining renal function. Analgesic withdrawal is therefore worth achieving even in the presence of advanced renal failure. Careful prolonged follow-up is required to prevent or detect relapse and to deal with the complications of prolonged renal failure, particularly bone disease and acidosis.Early diagnosis is life-saving in this condition. Attention is drawn to the diagnostic value of sterile pyuria, but the best screening test for the condition is careful interrogation of all patients with chronic renal disease of unknown aetiology; analgesic intake is rarely denied if asked for specifically.     

Analgesic Nephropathy: Clinical Syndrome and Prognosis

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

The nephrotoxicity of p-aminophenol. II. The effect of metabolic inhibitors and inducers.

Inducers and inhibitors of the microsomal mixed function oxidase system have no consistent effect upon the nephrotoxicity of p-aminophenol, or on binding of the compound in vivo to cell protein. p-[ring-3H]Aminophenol was bound in vitro to kidney microsomal protein and to a lesser extent to liver. The binding was enhanced by preincubation of the p-aminophenol in air and inhibited by ascorbate, GSH, N2 and NADPH. These findings indicate that in contrast to paracetamol hepatoxicity which is dependent upon the mixed function oxidase system, that nephrotoxicity of p-aminophenol is dependent upon oxidation to a toxic metabolite by some other pathway. A similar metabolite may be responsible for the nephrotoxic action of phenacetin.     

Papillary Necrosis in Rats Caused by Aspirin and Aspirin-containing Mixtures

Nearly half the rats gavage-fed with aspirin and aspirin-containing mixtures developed papillary necrosis in 20 weeks. This incidence is similar to that found in rats on A.P.C. mixtures with high and low concentrations of p-chloracetanilide, an impurity of phenacetin. Aspirin alone produced necrosis in 7 out of 19 rats (36·8%) whereas phenacetin in the same dose had failed to cause any renal damage over six to nine months. If these results also apply to man they suggest that aspirin and not phenacetin may be the major factor in analgesic nephropathy in patients taking A.P.C. mixtures. An augmented clearance of aspirin appeared to afford some protection to the medulla, and it is suggested that this observation may have important clinical and epidemiological applications.     

The nephrotoxicity of cisplatin

Cisplatin is a cancer chemotherapeutic agent whose clinical use is complicated by its dose related kidney toxicity. Since the histopathological profile of cisplatin nephrotoxicity appears similar to that of other heavy metals, it has been commonly presumed that cisplatin nephrotoxicity is related to the platinum moiety. However, the delayed time course and development of cisplatin nephrotoxicity is not characteristic of heavy metal nephropathy. Furthermore, cisplatin nephrotoxicity is stereospecific to the cis and not the trans isomer, indicating that the platinum atom is not the proximate nephrotoxicant. It is likely that a metabolite of cisplatin, possibly an aquated and/or hydroxylated complex, mediates the nephrotoxicity of cisplatin.     

Evidence of renal metabolism of ifosfamide to nephrotoxic metabolites

Nephrotoxicity is a limiting factor in the use of ifosfamide in children. Despite the co-administration of uroprotective agents such as sodium 2-mercaptoethanesulfonate (mesna), ifosfamide chemotherapy is associated with nephropathy characterized by glomerular toxicity and Fanconi syndrome in many children treated with this drug. This is in distinction to cyclophosphamide, an analogue which differs solely by the position of a chloroethyl group, and which is not associated with nephrotoxicity. We hypothesized that ifosfamide is metabolized by cytochrome P450 (CYP) enzymes located in the renal tubular cell to the toxic metabolite chloroacetaldehyde; and, that the higher production of chloroacetaldehyde from ifosfamide than from cyclophosphamide explains the clinical differences in nephrotoxicity. We found that in both pig renal cortical microsomes and whole human kidney microsomes incubated with 1 mM ifosfamide for 3 hr, 2 and 3 dechloroethylifosfamide (DCEI) were produced. Our study provides evidence that porcine and human kidney microsomes are capable of biotransforming ifosfamide to DCEI metabolites that are produced in equimolar amounts with chloroacetaldehyde, indicating that chloroacetaldehyde is locally produced by renal cells as a possible mechanism for nephrotoxicity.     

Protective Effect of Metalloporphyrins against Cisplatin-Induced Kidney Injury in Mice

Oxidative and nitrative stress is a well-known phenomenon in cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of two metalloporphyrins (FeTMPyP and MnTBAP), water soluble complexes, in cisplatin-induced renal damage and their ability to scavenge peroxynitrite. In cisplatin-induced nephropathy study in mice, renal nitrative stress was evident by the increase in protein nitration. Cisplatin-induced nephrotoxicity was also evident by the histological damage from the loss of the proximal tubular brush border, blebbing of apical membranes, tubular epithelial cell detachment from the basement membrane, or intra-luminal aggregation of cells and proteins and by the increase in blood urea nitrogen and serum creatinine. Cisplatin-induced apoptosis and cell death as shown by Caspase 3 assessments, TUNEL staining and DNA fragmentation Cisplatin-induced nitrative stress, apoptosis and nephrotoxicity were attenuated by both metalloporphyrins. Heme oxygenase (HO-1) also plays a critical role in metalloporphyrin-mediated protection of cisplatin-induced nephrotoxicity. It is evident that nitrative stress plays a critical role in cisplatin-induced nephrotoxicity in mice. Our data suggest that peroxynitrite is involved, at least in part, in cisplatin-induced nephrotoxicity and protein nitration and cisplatin-induced nephrotoxicity can be prevented with the use of metalloporphyrins.     

Nephrotoxicity after radionuclide therapies

Radioligand therapies have opened new treatment avenues for cancer patients. They offer precise tumor targeting with a favorable efficacy-to-toxicity profile. Specifically, the kidneys, once regarded as the critical organ for radiation toxicity, also show excellent tolerance to radiation doses as high as 50–60 Gy in selected cases. However, the number of nephrons that form the structural and functional units of the kidney is determined before birth and is fixed. Thus, loss of nephrons secondary to any injury may lead to an irreversible decline in renal function over time. Our primary understanding of radiation-induced nephropathy is derived from the effects of external beam radiation on the renal tissue. With the growing adoption of radionuclide therapies, considerable evidence has been gained with regard to the occurrence of renal toxicity and its associated risk factors. In this review, we discuss the radionuclide therapies associated with the risk of nephrotoxicity, the present understanding of the factors and mechanisms that contribute to renal injury, and the current and potential methods for preventing, identifying, and managing nephrotoxicity, specifically acute onset nephropathies.     

Possible Role of Laxatives in Analgesic Nephropathy

Eight out of ten of patients with analgesic nephropathy were regular and usually heavy laxative takers compared with 12 out of 200 controls from the general population and four out of 70 patients attending a renal clinic. The finding that regular laxative taking was greatly increased in patients with analgesic nephropathy suggests that this condition may often be due to the combined abuse of both laxatives and analgesics. In a series of 40 patients with rheumatoid arthritis all were found to have normal renal function and no patient took laxatives regularly. This finding would explain why analgesic nephropathy is so uncommon in patients with rheumatoid arthritis despite the fact that they are regular and heavy analgesic takers.     

Phenacetin Nephropathy

Four patients who had ingested large amounts of phenacetin-salicylate medications were studied during a 12-month period. Renal failure had progressed slowly over a number of years. All patients took the drug because of psychogenic headache. Considerable skill was required to elicit the history of drug habituation. The major features of the nephropathy were multiple episodes of metabolic acidosis, minimal proteinuria, pyuria but no bacteriuria, and polyuria and polydipsia early in the course of drug ingestion. Papillary necrosis was not a prominent clinical feature of this series. Discontinuation of drug ingestion by one patient was associated with recovery of a considerable degree of renal function. Preliminary experimental evidence obtained in the dog suggests that salicylate impaired the efficiency of the counter-current multiplier by decreasing sodium transport in the ascending limb of Henle, and decreased the permeability to water of the distal convoluted and collecting tubule; phenacetin had no such effect.     

Consequences associated with nonnarcotic analgesics in the fetus and newborn

Nonnarcotic analgesics include well-known, widely used substances such as acetylsalicylic acid (ASA) and acetaminophen. ASA is a potent inhibitor of prostaglandin synthesis, and this mechanism is responsible for many potential toxicities in the fetus and newborn. These may include bleeding, altered renal function, and constriction of the ductus arteriosus in addition to analgesia. As such, ASA is frequently avoided during gestation and the immediate neonatal period. Acetaminophen is less well recognized as an agent with activity outside the central nervous system. It does not possess antiinflammatory activity like other substances that inhibit prostaglandins but has been shown to be an analgesic with potency comparable to ASA. This is believed to be by inhibition of brain prostaglandin synthetase. We have determined by using the chronically catheterized sheep fetus that acetaminophen has potent activity on the ductus arteriosus and produces a constriction, in therapeutic analgesic quantities, comparable to ASA. Thus, acetaminophen may be a potent inhibitor of prostaglandin function in the fetus.     

Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria

Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea-cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition.     

Differential effects of tannic acid on cisplatin induced nephrotoxicity in rats

Cisplatin is a widely used antineoplastic drug. Major drawback of cisplatin therapy is its nephrotoxicity. The objective of this study was to check the effect of tannic acid on cisplatin induced nephrotoxicity. Post-treatment of tannic acid prevents cisplatin (5mg/kg) induced nephrotoxicity and decreases poly(ADP-ribose) polymerase cleavage, phosphorylation of p38 and hypoacetylation of histone H4. In contrast, co-treatment of tannic acid potentiates the nephrotoxicity. Comparative nephrotoxicity studies show that co-treatment of tannic acid with reduced dose of cisplatin (1.5mg/kg) developed almost similar nephrotoxicity. MALDI protein profiling of plasma samples provides indirect evidence that tannic acid co-treatment increases bioavailability of cisplatin.     

Argininosuccinic aciduria: prenatal studies in a family at risk.

We have monitored two successive pregnancies in a family which we found to be at risk for argininosuccinic aciduria. We measured argininosuccinic acid (ASA) concentrations in amniotic fluid and utilized an indirect assay of ASA lyase activity in cultured amniotic fluid cells. The assay procedure is based on the uptake of 14C from [14C]citrulline and of [3H]leucine into protein. ASA was easily measured in amniotic fluid from the first fetus at risk, whereas none was detectable in control fluids. Amniotic fluid cells cultured from this fetus had only 5.5% of control ASA lyase activity. The pregnancy was terminated, and hepatic ASA lyase activity in the fetus was shown to be about 1.3% of control values. In addition, eight fetal tissues were analyzed for ASA, and all had significant accumulation. ASA was not detected in amniotic fluid from the second fetus at risk, and ASA lyase activity in cultured cells was 80% of control activity. Enzymatic analysis of erythrocyte lysate confirmed the diagnosis of an unaffected child (ASA lyase = 46% of control) and indicated heterozygosity. Thus, we provide further evidence that argininosuccinic aciduria can be diagnosed successfully in utero by indirect assay of ASA lyase activity in cultured amniotic fluid cells. In addition, high amniotic fluid ASA concentrations provide strong adjunctive evidence for such a prenatal determination, and may prove to be sufficient for diagnosis.