Editorial Nsaids and Nephrotic Syndrome

Editorial

Evangelina Me´rida1 and Manuel Praga1,2 CJASN 14: 1280–1282, 2019. doi: https://doi.org/10.2215/CJN.08090719

The association between nonsteroidal anti-inﬂammatory result in an increased conversion of arachidonic acid drugs (NSAIDs) and nephrotic syndrome has long to leukotrienes, which could activate T-helper cells

been recognized. Minimal change disease and mem- and induce a diffuse podocyte damage. However, no 1 fi Division of branous nephropathy have been the most common studies have con rmed this hypothesis. Nephrology, Instituto findings in those patients in whom a kidney biopsy In most patients, NSAIDs-related minimal change de Investigacioń was performed (1–6). Regarding NSAIDs-related min- disease resolves after drug discontinuation, which Hospital 12 de imal change disease, it is a peculiar type of nephrotic is accompanied in some patients by a short course of Octubre, Madrid, – Spain; and syndrome in which most of reported patients present corticosteroids (1 4). It has been reported that early 2Department of with a severe AKI accompanying nephrotic syndrome treatment with corticosteroids can induce a more Medicine, manifestations (edema, proteinuria .3.5 g/d, and rapid and efficient recovery of kidney function Complutense hypoalbuminemia). Kidney biopsies typically show in NSAIDs-induced AIN accompanied or not by University, Madrid, Spain the characteristic pattern of drug-induced acute inter- nephrotic proteinuria (8). stitial nephritis (AIN): a diffuse interstitial infiltrate Paradoxically, NSAIDs induce a marked reduction Correspondence: composed predominantly of T lymphocytes, although of proteinuria in different types of nondiabetic glo- Dr. Manuel Praga, eosinophils, macrophages, and plasma cells can also merular nephropathies and can potentiate the anti- Instituto de be observed (7). The glomeruli are normal in light proteinuric effect of renin-angiotensin blockers (9). Investigacioń Hospital microscopy, but a diffuse effacement of podocyte foot Changes in glomerular hemodynamic through a pre- 12 de Octubre, i + 12, – Avda Co´rdoba s/n, processes is observed in electron microscopy (1 4). glomerular vasoconstriction and an improvement 28041 Madrid, Spain. NSAIDs-related minimal change disease could be, of the glomerular protein permselectivity have been Email: mpragat@ therefore, categorized as a complication of NSAIDs- invoked to explain this effect. However, the frequent senefro.org induced AIN. However, a “pure” nephrotic syndrome side effects of NSAIDs have prevented their clinical has been described in some patients taking NSAIDs, use for the treatment of glomerular diseases. with diffuse fusion of foot processes but no accom- Nephrotic syndrome with a histopathologic pattern panying interstitial infiltrates. In some patients, of membranous nephropathy, a paradigmatic type tubular necrosis without interstitial infiltrates has of immune complex glomerular disease, is another been the most salient histopathologic finding. Pa- side effect of NSAIDs, and different types of conven- tients with AIN accompanied by minimal change tional and selective NSAIDs have been reported as diseasehavebeenreportedwithavarietyofcon- causatives of this complication (1,5,6). The presence of ventional NSAIDs and selective COX-2 inhibitors. electron-dense subepithelial deposits along the glo- As usual in NSAIDs-induced AIN, the extrarenal man- merular capillary loops and a complete effacement of ifestations (low-grade fever, skin rash, and eosinophilia) foot processes were the most characteristic findings in that frequently accompany AIN induced by antibiotics kidney biopsies (5,6). Unlike NSAIDs-related mini- and other drugs are characteristically absent (7). mal change disease, inflammatory interstitial infil- Although NSAIDs are one of the most frequent trates were absent in most reported patients. This causes of drug-induced AIN, the incidence of ne- histologic difference explains why most of the pa- phrotic syndrome seems to be low. In two patient tients with NSAIDs-induced minimal change disease series of drug-induced AIN, only three patients of a present with nephrotic syndrome accompanied by total of 121 showed nephrotic-range proteinuria, al- severe AKI, whereas nephrotic syndrome with nor- though NSAIDs were the offending drug in 40% of the mal kidney function is the most frequent presentation patients (7). However, patients with NSAIDs-related in NSAIDs-induced membranous nephropathy. AIN tend to present higher proteinuria values than Immunostaining for the different subclasses of IgG other types of drug-induced AIN, although they rarely can help to differentiate NSAIDs-induced membra- reach the nephrotic range (7,8). Notably, nephrotic nous nephropathy from primary forms of the disease. syndrome and nephrotic-range proteinuria seem to As in other types of secondary membranous nephrop- be a specific complication of NSAIDs, because they athy, deposition of IgG1 has been reported in patients have been only exceptionally reported with other types with cases associated with NSAIDs (5), whereas de- of drug-induced AIN. To explain this susceptibility for position of IgG4 is characteristic of primary forms. The proteinuria, it has been suggested that a decrease in the pathogenesis of membranous nephropathy associated synthesis of prostaglandins induced by NSAIDs could with NSAIDs is unknown. Glomerular deposition of

antigens bound to NSAIDs could elicit an immune re- not a statistically significant trend among patients with a sponse, although these drugs could also exacerbate or past use (.2 months to 2 years). trigger autoimmune reactions against podocyte antigens. This study is the first systematic analysis of the Intriguingly, positive immunostaining for PLA2R has been association between NSAIDs consumption and the risk reported in a patient with membranous nephropathy pre- of developing a nephrotic syndrome. Its conclusions are cipitated by piroxicam, although serum anti-PLA2R was not clinically relevant, although several important caveats available (5). should be taken into account. One of them is the inev- The incidence of NSAIDs-related membranous nephrop- itable chronological imprecision when analyzing drugs, athy could be greater than suspected according with the like conventional NSAIDs, that are frequently avail- study of Radford et al. (6). They reported 125 patients with able over the counter and consumed in a discontinuous early membranous nephropathy (stages 1 and 2 membra- mannerbyalargenumberofnormalsubjects.Addition- nous nephropathy with small subepithelial deposits). ally, the accuracy of the diagnosis of nephrotic syndrome Twenty-nine of them were taking NSAIDs at the time of using pre-established codes should be taken with cau- diagnosis, of which 13 (10%) fulfilled the criteria defined by tion in studies like this that involve a large number of the authors to establish the diagnosis of NSAIDs-related patients over a long period of time. The criteria used to membranous nephropathy: onset of the nephrotic syn- establish the diagnosis of nephrotic syndrome are not drome while taking NSAIDs, exclusion of other causes of reported, and therefore, we do not know if all included secondary membranous nephropathy, and rapid disap- patients presented a proteinuria .3.5 g/d accompanied pearance of proteinuria after NSAIDs withdrawal (6). by hypoalbuminemia. Interestingly and reinforcing the causal association be- A major constraint of the study is the low percentage of tween NSAIDs and nephrotic syndrome, relapses of pro- patients with histologic confirmation of kidney disease. teinuria have been reported after re-exposure to NSAIDs, Although patients 18 years old or younger were excluded and in some patients, re-exposure was to a type of NSAIDs (another limitation of the study), a kidney biopsy was different from the one causing the first episode of nephrotic performed in only 11% of the patients, despite the fact that syndrome (5). kidney biopsy is considered a central tool in the diagnostic In this issue of CJASN, Bakhriansyah et al. (10) describe workup of most adult patients presenting with nephrotic the results of a systematic observational matched patient- syndrome. The list of histologic diagnoses is somewhat control study about the association between NSAIDs and surprising, because only a minority of patients (15 of 167) nephrotic syndrome. The study used data from the Clinical taking NSAIDs and presenting a nephrotic syndrome re- Practice Research Datalink, a general practitioner database ceived the diagnosis of minimal change disease or AIN, and of the United Kingdom National Health Service. Patients other diagnoses (for instance, crescentic or mesangiocapil- had a diagnosis of nephrotic syndrome established in the lary GN) have no apparent pathogenic relationship with period 1989–2017, and controls were patients without these drugs. nephroticsyndromebeforeandatthedateofdiagnosis The study of Bakhriansyah et al. (10) raises questions of nephrotic syndrome in matching cases. Exposure to of great clinical importance for the clinician. Are we NSAIDs was divided into current use (NSAIDs prescrip- overlooking patients with NSAIDs-induced nephrotic tion within the last month before the date of diagnosis), syndrome? If so, are we prescribing long courses of recent use (prescription within 1–2 months before), or past immunosuppressive treatments to patients with mini- use (prescription .2 months before). According to the mal change disease or membranous nephropathy caused duration of NSAIDs exposure, current use was divided by NSAIDs that would have resolved with the discon- into use of 1–14, 15–28, or .28 days. Patients with past tinuation of the drug accompanied perhaps by a short use were divided into those in whom NSAIDs had been course of corticosteroids? Considering that the existing discontinued between 2 months and 2 years before the literature on this topic is in general old and scarce, with only date of diagnosis and those with an NSAIDs discontinu- patient reports or short series of patients published, data ation .2 years. NSAIDs were classified as acetic acid de- from this study should encourage nephrologists to, on one rivatives (such as indomethacin, ketorolac, and diclofenac), hand, carefully review the current or recent intake of propionic acid derivatives (such as naproxen, ibuprofen, NSAIDs in any patient with nephrotic syndrome, particu- and ketoprofen), selective COX-2 inhibitors (coxibs), larly when minimal change disease or membranous ne- fenamates, and oxicams, and other NSAIDs. phropathy is found in kidney biopsies, and on the other A total of 2620 patients and 10,454 matched controls hand, perform collaborative studies to collect large series of were included in the analysis. The results show that current patients with unequivocal diagnosis of NSAIDs-induced use for .2 weeks, recent use, and past use (discontinuation nephrotic syndrome to identify their differential clinical and .2 months to 2 years) of conventional NSAIDs (acetic acid histopathologic characteristics and delineate their more and propionic acid derivatives) were associated with a efficient treatment. Basic research about the pathogenic fi signi cantly higher risk of nephrotic syndrome (adjusted mechanisms through which NSAIDs cause glomerular fi odds ratio, 1.34; 95% con dence interval, 1.06 to 1.70; damage is also needed. adjusted odds ratio, 1.55; 95% confidence interval, 1.11 to 2.15; and adjusted odds ratio, 1.24; 95% confidence interval, Disclosures 1.07 to 1.43, respectively) compared with nonuse and that Dr. Praga has received personal fees for lectures from Alexion, the risk disappeared after 2 years of discontinuation. The Fresenius, Otsuka, and Retrophin and grant support and personal use of selective COX-2 inhibitors was not associated with fees from Alexion, outside of the submitted work. Dr. Mérida has a higher risk of nephrotic syndrome, although there was nothing to disclose. 1282 CJASN

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