Henry Ford Hospital Medical Journal

Volume 31 Number 2 Article 10

6-1983

Drug-Induced Glomerulopathy: A Selective Review

Francis Dumler

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Recommended Citation Dumler, Francis (1983) "Drug-Induced Glomerulopathy: A Selective Review," Henry Ford Hospital Medical Journal : Vol. 31 : No. 2 , 110-114. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol31/iss2/10

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Henry Ford Hosp Med J Vol 31, No 2,1983 .Review Article Drug-Induced Glomerulopathy: A Selective Review

Francis Dumler, MD"

Tbe pathogenesis of drug-induced glomerular disease is ficiency. Drugs which cause tubular necrosis are excluded. becoming better understood because of recent ad­ Nonsteroidal anti-inflammatory agents are examples of vances in the study of glomerular physiology and meta­ drugs that induce glomerular proteinuria and minimal boUsm. Various classes of drugs may produce nephro­ change nephropathy. Gold, penicillamine, and capto- toxicity. This review is Umited to types of drugs whose pril produce drug-induced glomerular proteinuria in use may result in glomerular functional and metabolic association with membranous nephropathy. Finally, abnormalities leading to proteinuria and/or renal insuf­ semustine and mitomycin are examples of drugs that induce glomerular sclerosis and microangiopathy.

Recent advances in the study of glomerular physiology proteins decreases, reaching very low values when the and metabolism have increased our understanding of the size of albumin (36°A) is approached. Neutral dextrans pathogenesis of drug-induced glomerular disease. Var­ with a molecular size similar to that of albumin have a ious types of therapeutic agents are associated with renal significantly higher fractional clearance than albumin. dysfunction. Nephrotoxicity that results in acute renal However, negatively charged sulphated dextrans have a failure is usually dramatic in its clinical presentation, is lower clearance than neutral dextrans ofsimilar size, and well recognized, and has been comprehensively reviewed approach that of albumin (4,5). Drugs or drug metabo­ (1,2). By contrast, drug-induced glomerulopathy is clini­ lites which affect glomerular metabolism and disrupt the cally more insidious, and progressive proteinuria or renal structural or molecular integrity of the glomerular filtra­ insufficiency develop gradually. The nonsteroidal anti­ tion barrier may also cause glomerulopathy and signifi­ inflammatory agents and the angiotensin converting cant proteinuria. For example, in rats, the parenteral enzyme inhibitor captopril have been selected as exam­ administration of puromycin aminonucleoside induces ples of drugs that induce proteinuria. Although they have proteinuria, hypoalbuminemia, hypercholesterolemia, been used in general clinical practice for a relatively short and a renal lesion similar to that of human minimal time, their use is increasing. Gold and penicillamine are change nephropathy (6-8). In this experimental model, a drugs that induce membranous glomerulopathy, and diminution of the electrostatic barrier function of the semustine and mitomycin C are chemotherapeutic agents glomerular capillary wall (9,10) and loss of glomerular that induce glomerular sclerosis. polyanionic sites (11,12) have been well documented. Cellular metabolic damage induced bythis agent results To better understand the pathogenesis of drug-induced in a loss of polyanion coating and subsequent proteinuria. proteinuria, a briefdescription ofthe normal filtration of plasma proteins by the glomerulus is in order. Plasma Nonsteroidal Anti-inflammatory Drugs proteins that appear in the urine must be transferred Currently, at least 14 nonsteroidal anti-inflammatory across the glomerular filter through a pathway consist­ ing of the endothelial fenestrae, the glomerular base­ agents are available in the United States to treat arthritis ment membrane, and the slit diaphragm of the epithelial and musculoskeletal pain of various etiologies. These cell. A polyanion coating of sialic acid renders a highly drugs share the ability to block prostaglandin synthesis negative charge on the endothelial and epithelial cell in various tissues (13). The use of these agents may be coats and to the glomerular basement membrane (3).

Submitted for publication: October 11,1982 Molecular size and charge are important determinants Accepted for publication: May 9,1983 of the glomerular filtration of proteins. As the effective •Department of Internal Medicine, Division of Nephrology, Henry Ford Hospital molecular radius increases, the fractional clearance of Address reprint requests to Dr. Dumler, Henry Ford Hospital, 2799 W Crand Blvd, Detroit, Ml 48202.

110 Drug-Induced Glomerulopathy

associated with decreased renal function due to inhibi­ Gold and Penicillamine tion of prostaglandin synthesis, which results in a pre­ Proteinuria may occur in up to 7% of individuals who dominance of vasoconstrictor effects on the glomerular receive parenteral gold therapy for rheumatoid arthritis, microcirculation of patients treated with these drugs. At and the nephrotic syndrome may develop in as many as particularly high risk for acute renal failure are those 3% of patients (27). The renal histological lesion is usually with preexisting renal disease, volume depletion (espe­ that of membranous nephropathy with granular depos­ cially following diuretic therapy), or cardiac insuffi­ its of IgG and IgM alongthe glomerular capillary wall. In ciency; these conditions result in decreased renal perfu­ addition, characteristic filamentous electron dense cyto­ sion pressure and increased renal vasoconstrictor activity plasmic inclusions commonly occur; in some cases, from activation ofthe renin-angiotensin system (14-17). these have been demonstrated by x-ray dispersion anal­ Hyperkalemia may be quite prominent even when loss ysis to be gold particles (28,29). of renal function is not severe (18,19), perhaps due to a concomitant decrease in renin-aldosterone production Mechanisms for development of this nephropathy are (20). In some patients, histological evidence of acute not clear. Discovery of a mechanism is hampered by the tubulo-interstitial nephritis has been reported during occurrence of membranous nephropathy in patients acute renal failure (21,22). with rheumatoid arthritis who have not been exposed to gold therapy (30). Thus, a direct toxic effect of gold on Differing degrees of glomerular proteinuria have been the glomerulus cannot be excluded. Also, gold therapy reported with the nonsteroidal anti-inflammatory drugs may result in the release of renal tubular epithelial anti­ indomethacin, naproxen, fenoprofen, tolmetin, and gens (31) and subsequent immune complex formation sulindac (15,16,21-25), and histological changes are con­ leading to glomerular damage (32). The potential for sistently similar to those of minimal change nephropathy developing the immunological response that leads to (lipoid nephrosis). No systematic studies have been car­ membranous glomerulopathy may well be genetically ried out on the glomerular polyanion content in these controlled, since rheumatoid arthritis patients who are patients, and little data are available on the effects of HLA-DRw3 positive have a 32-times greater risk of nonsteroidal anti-inflammatory drugs on glomerular developing proteinuria during gold therapy than patients metabolism other than on prostaglandin synthesis. In who are HLA-DRw3 negative (33). one study, indomethacin was found to decrease glo­ merular basement membrane collagen synthesis (26). Nephrotic syndrome and membranous glomerulopathy Thus, these agents may induce proteinuria by a toxic have also been reported after oral gold therapy. How­ effect on the cells responsible for the integrity of the ever, the reported experience of only a few cases of glomerular filtration barrier. mild proteinuria occurring in over 1672 patients treated for at least six months suggests that the overall preval­ Patients who receive these agents, particularly those at ence of proteinuria may be less than with parenteral high risk because of diuretic therapy, volume depletion, gold therapy (34). preexisting renal disease, high renin hypertension volume depletion, or congestive heart failure, should have regu­ In a multicenter trial, penicillamine was shown to be lar evaluation of their renal function and routine urinal­ effective in rheumatoid arthritis (35), but the authors of ysis during therapy. Gradually progressive renal insuffi­ this report noted that nephrotoxicity precludes the ciency, sudden increases in serum creatinine or potassium, indiscriminate use of penicillamine to treat rheumatoid or the presence of proteinuria greater than 500 mg/day arthritis. The prevalence of penicillamine-induced pro­ are sufficient indications to discontinue therapy. In teinuria in rheumatoid arthritis patients is 7-20% (36,37). patients who develop proteinuria, the need for nonste­ On renal biopsy, the lesion is usually consistent with the roidal anti-inflammatory therapy should be reassessed. diagnosis of membranous glomerulopathy, and in most If no adequate alternatives are present, continuation of patients circulating immune complexes are not detected therapy may be reasonable in rare instances, provided (36). These abnormalities are similar to those observed in close monitoring of renal function and proteinuria are patients receiving gold therapy. Rheumatoid arthritis concomitantly carried out. If renal insuffiency or pro­ patients who are HLA-DRw3 positive are also at a higher teinuria develop while the patient is under treatment risk of nephrotoxicity from penicillamine therapy (33), as with one of these agents, it is possible that similar com­ they are from gold therapy. Chelation of penicillamine plications may be encountered when another nonste­ by iron in the intestine reduces its absorption, and in roidal anti-inflammatory drug is used. patients taking iron supplements renal toxicity may be apparent only after discontinuation of iron therapy

111 Dumler

increases penicillamine absorption (38). Patients with During captopril therapy, proteinuria occurs in approx­ gold-induced proteinuria are also at a higher risk of imately 1.5% of patients, and nephrotic syndrome progressive proteinuria during penicillamine therapy (39). develops in 0.4% (49). On renal biopsy, the usual histo­ The nephropathy associated with gold and penicilla­ logical lesion is that of membranous nephropathy (49- mine therapy in patients with rheumatoid arthritis is 51). The pathogenesis of captopril-induced glomerulo­ likely to be immunologically mediated. As in idiopathic pathy is probably similar to that of gold and penicillamine, membranous glomerulopathy, the lesion may result that is, immune complex nephropathy. While these from the glomerular deposition of preformed immune drugs share a heavy metal or a heavy metal binding site, complexes. These are formed from the reaction of circu­ it is not clear how the immune complex nephropathy is lating antibodies to antigens extrinsic to the glomerulus generated. In some patients, proteinuria may result in that become bound to the glomerulus during the disease spite of continuous captopril therapy (49), but no data process (40). The possibility that immune complexes are available on how frequently this occurs. Membran­ form in situ has recently been postulated in the patho­ ous nephropathy has also been found in random renal genesis of membranous nephropathy (40). biopsies of patients without proteinuria who have been treated with captopril for severe hypertension (51). In general, proteinuria will develop within three to 12 months of initiating therapy with gold or penicillamine In patients treated with captopril, the advantages of the (39). After therapy has been discontinued, proteinuria drug must be weighed against its potential nephrotoxic­ usually decreases, although this may take several months ity. In patients with bilateral renal artery stenosis or a (27,35,36). When the drugs are discontinued, the glomer­ solitary kidney and renovascular hypertension, therapy ulopathy rarely progresses, and renal insufficiency is should be gradual and cautious in order to minimize the uncommon (27,35,36). Because improvement in the risk of acute renal failure. In those patients in whom degree of proteinuria has been reported with steroid persistent proteinuria of 0.5-1.0 gm/day or greater therapy (27), a short course of prednisone might be occurs, renal biopsy should be considered and the drug given to patients with gold or penicillamine-induced should be discontinued, particularly when renal func­ membranous glomerulopathy, as is currently advocated tion is already impaired. In patients with renal failure, for idiopathic membranous nephropathy (41). Mild pro­ hyperkalemia due to aldosterone deficiency is also more teinuria of less than 500 mg/day is not an indication for likely to occur (52). Perhaps the use of smaller doses (i.e., discontinuing therapy (36), but proteinuria greater than 100 mg/day or less) than those currently recommended 0.5-1.0 mg/day or declining renal function requires may provide comparable blood pressure control and prompt discontinuation of therapy. On some occasions reduce the likelihood of side effects, particularly in reintroduction of the drug has led to recrudescence of patients with renal insufficiency (53). the nephrotic syndrome (42). Semustine (methyl-CCNU) Captopril The chlorethyl nitrosoureas are antitumor agents of par­ Administration of captopril has rarely been associated ticular use to treat solid tumors. Although initial studies with acute renal failure, which, when it occurs, has been did not show significant nephrotoxicity (54) with the use attributed to a concomitant decrease in blood pressure of semustine, in one study severe renal damage was (43). However, some investigators have suggested a reported several years later in all six children who direct nephrotoxic effect, because loss of renal function received more than 1500 mg/m^ (55). In another study, during captopril treatment may occur in the absence of decreased renal function occurred in 26% of adult hypotension and because histological study discloses patients who received more than 1400 mg/m^, and patchy atrophy and inflammation (44). A report of eosin­ severe chronic renal failure occurred in 14% (56). Histo­ ophil ia, eosi noph ilu ria, and acute renal failure observed logically, glomeruli revealed significant sclerosis, with simultaneously in a patient receiving captopril suggests thickening and wrinkling of the glomerular basement that hypersensitivity phenomena may be important in membrane as well as marked interstitial fibrosis and the development of acute renal failure (45). Also, patients moderate lymphocytic infiltration (55,56). Since the with bilateral renal artery stenosis or renal artery stenosis compound is rapidly metabolized, either the active drug in a solitary kidney are at particular risk for developing or a metabolite could be responsible for the nephrotox­ acute renal failure during captopril therapy (46-48), icity, but the nature of the aaive drug or its metabolites probably because of inadequate autoregulation of glo­ is not known. Semustine should be used only when the merular filtration in the presenceof reduced renal artery ratio of therapeutic benefit to renal toxicity is consi­ perfusion pressure. dered to be high. Close monitoring of renal function

112 Drug-Induced Glomerulopathy

including urinalysis, urea nitrogen, serum creatinine, markedly aggravated by the use of blood transfusions and creatinine clearance should be carried out before (60).* Renal histological studies have demonstrated typi­ each treatment and regularly after therapy is completed. cal microangiopathy with significantfibrin deposition in All other potential nephrotoxicagentsshould be avoided, small vessels (53,54). and therapy should be discontinued if lossof renal func­ tion is noted (56). Summary The nonsteroidal anti-inflammatory drugs, gold, penicil­ Mitomycin C lamine, captopril, semustine, and mitomycin C are Recent reports have indicated that adjuvant therapy examplesof drugs whose use may be associated with the with 5-fluorouracil and mitomycin C for malignancy is development of significant glomerular disease leading associated with a syndrome characterized by progres­ to proteinuria and renal insufficiency. Patients who sive microangiopathic hemolytic anemia, disseminated undergo therapy with these drugs should be monitored intravascular coagulation, and acute renal failure (57,58). with routine urinalysis and serum creatinine determina­ This syndrome may also occur when mitomycin C is used tions. The appearance of persistent glomerular protein­ alone (59). Therapy with these agents may result in a uria requires reassessment of the benefit-to-risk ratio of hemolytic-uremic syndrome which is suddenly and the drug therapy, while loss of renal function warrants discontinuation of the drug.

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