Nephrotic-range Proteinuria and Interstitial Nephritis Associated with the Use of a Topical Loxoprofen Patch

Transcription

1 CASE REPORT Nephrotic-range Proteinuria and Interstitial Nephritis Associated with the Use of a Topical Loxoprofen Patch Hiroaki Kikuchi, Makoto Aoyagi, Kiyotaka Nagahama, Yu Yajima, Chisato Yamamura, Yohei Arai, Suguru Hirasawa, Shota Aki, Naoto Inaba, Hiroyuki Tanaka and Teiichi Tamura Abstract A 76-year-old woman with a history of lumbar fracture and marked proteinuria, bilateral pitting edema, malaise and pruritus was referred for an evaluation of an impaired renal function. A renal biopsy led to a tentative diagnosis of acute interstitial nephritis (AIN) with minimal change disease caused by nonsteroidal antiinflammatory drugs (NSAIDs). Following the discontinuation of oral NSAIDs, the patient s symptoms disappeared spontaneously. However, nephrotic-range proteinuria relapsed one month after discharge, following loxoprofen patch use. The withdrawal of the topical loxoprofen patches once again resulted in the disappearance of all symptoms. This is the first case report of nephrotic-range proteinuria and AIN secondary to topical NSAID patch use. Key words: topical patch, nephrotic-range proteinuria, nonsteroidal anti-inflammatory drugs (Intern Med : -, ) () Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs), although commonly used, are well known to have the potential to cause nephrotoxicity, such as fluid and electrolyte abnormalities (), acute renal failure (), nephrotic syndrome, interstitial nephritis and renal papillary necrosis (). Hence, topical NSAIDs were developed in order to minimize the incidence of systemic adverse events, including gastrointestinal disorders and renal toxicity. However, despite the safety of topical NSAIDs compared to oral NSAIDs, several reports have documented the occurrence of renal disease in association with the use of topical NSAID gel (, ). More recently, a topical patch containing the NSAID loxoprofen was developed, using a novel delivery system that dispenses therapeutic doses of the drug directly to the affected site. Similar to other topical NSAID formulations, it produces its therapeutic effect by releasing its constituents in small quantities into the systemic circulation (6). To the best of our knowledge, despite its systemic absorption, no case reports of nephrotic syndrome occurring in association with the use of topical NSAID patches have been published to date. We herein report a case of nephrotic-range proteinuria and acute interstitial nephritis caused by topical loxoprofen patch use. Case Report A 76-year-old woman, who was previously in good health, presented with increasing edema of both legs, anorexia, and pruritus and was referred for an evaluation of renal impairment and nephrotic syndrome. She had no significant past medical history other than hypertension, hyperlipidemia and atypical mycobacterial disease, no history of smoking and no significant family history. Her current medications included nifedipine, propranolol hydrochloride, pitavastatin calcium and levofloxacin hydrate. Six months Department of Nephrology, Yokosuka Kyosai Hospital, Japan and Department of Pathology, Yokohama City University, School of Medicine, Japan Received for publication August 9, ; Accepted for publication January, Correspondence to Dr. Hiroaki Kikuchi, hiroaki.k@gmail.com

2 Table. Laboratory Data on First Admission Blood counts Serology White blood cell,8 / L IgG 98 mg/dl Neutrophil 68.8 % IgA mg/dl Lymphocyte 8.9 % IgM mg/dl Monocyte. % IgE 9 IU/mL Eosinophil. % CH 6 CH/mL Basophil. % CRP.7 mg/dl Red blood cell 79 / L RA < IU/mL Hemoglobin 9. g/dl ANA - Platelet.6 / L P-ANCA < EU C-ANCA < EU Blood chemistry ASO 7 IU/mL Sodium 7 meq/l Potassium. meq/l Urinalysis Chloride 8 meq/l Protein 7.6 g/day Urea nitrogen mg/dl Occult blood (-) Creatinine. mg/dl Glucose (-) Total protein 6. g/dl Sediment Albumin. g/dl RBC - /HPF AST 9 IU/L WBC - /HPF ALT IU/L Epithelial cast - /HPF Glucose mg/dl Granular cast -9 /HPF T. Chol 8 mg/dl LDL Chol 67 mg/dl MG 8,6 g/l NAG 9.9 U/L AST: aspartate aminotransferase, ALT: alanine aminotransferase, Chol: cholesterol, CH: % hemolytic complement unit, CRP: C-reactive protein, RF: rheumatoid factor, ANA: anti-nuclear antibody, P-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, C-ANCA: serine proteinase -anti-neutrophil cytoplasmic antibody, ASO: anti-streptolysin O antibody, MG: beta--microglobulin, NAG: N-acetyl- -D-glucosaminidase Figure. Normocellular glomeruli without marked thickening of the basement membrane (periodic acid-schiff, original magnification ). Figure. Renal biopsy specimen showing normal glomeruli and diffuse infiltration of the renal interstitium with inflammatory cells (Trichrome, original magnification ). prior to her clinical presentation, she suffered a lumbar fracture due to a fall, after which she began to take lornoxicam continuously for back pain. At that time, she had no albuminuria, and her serum creatinine level was.8 mg/dl. In early July, she presented to the department of nephrology with a blood pressure of 9/88 mmhg, a pulse rate of 6 beats per minute and a body weight of 8.6 kg. A physical examination revealed marked pitting edema of both legs, with facial swelling. The laboratory data were significant for a relatively low serum albumin level and an elevated serum creatinine level of. mg/dl (Table). The NSAIDs were subsequently discontinued, and she was admitted for a renal biopsy under echo guidance. On admission in mid July, a differential leukocyte count demonstrated no eosinophilia. A urinalysis indicated a specific gravity of.8 and + proteinuria. A -hour urine collection showed protein excretion of 7.6 g (Table). The ASO and anti-nuclear antibody titers were negative, and the % hemolytic complement (CH) level was normal. Serum protein electrophoresis demonstrated no monoclonal spikes. Immunologic and various infectious serologic tests were negative (Table). Renal ultrasound showed that both kidneys were normal in size. Light microscopy of the renal biopsy specimen demonstrated no conspicuous glomerular abnormalities (Fig. ). There was mild interstitial fibrosis and focal interstitial inflammatory infiltrates, predominantly consisting of mononuclear cells (Fig. ). Immunofluorescence microscopy did not

3 Figure. Electron micrograph showing focal effacement of glomerular foot processes (black arrows) without deposits or basement abnormalities (original magnification,) Lornoxicam Albmin (g/dl) Cre (mg/dl) Loxoprofen patch Biopsy U-pro (g/day or g/gcre) Jan Apr Jul Oct Feb Figure. Clinical course of the albumin, urine protein and serum creatinine levels. Cre: serum creatinine, U-pro: urinary protein, g/gcr: urinary protein to urinary creatinine ratio..... reveal any immune complex deposits. Electron microscopy (Fig. ) disclosed local effacement of the glomerular foot processes, without deposits or basement membrane abnormalities. Based on these findings, a pathologic diagnosis of interstitial nephritis with minimal change disease (MCD), likely caused by NSAIDs, was made. The nephrotic-range proteinuria rapidly resolved following the withdrawal of lornoxicam, without the administration of steroids or cytotoxic therapy. Two weeks later, the patient had symptomatically improved, her kidney function had recovered completely (Fig. ) and a urinalysis showed no abnormal findings. Hence, she was discharged under the recommendation of subsequent outpatient follow-up. One month later, however, she again presented with recurrence of peripheral edema, severe anorexia and pruritus, despite the discontinuation of all oral and enteral NSAIDs and over-the-counter medications (second admission). A physical examination revealed marked bilateral pitting leg edema. The laboratory data demonstrated a re-elevated serum creatinine level of.8 mg/dl (Fig. ), a serum albumin level of. g/dl and a serum total protein level of.8 g/dl, and a urinalysis showed + protein with a protein-to-creatinine ratio of.6 (Fig. ). No candidate lesions accounting for the anorexia were found on upper gastrointestinal tract endoscopy, abdominal ultrasound or abdominal computed tomography. Upon extensive questioning regarding her medications, however, she reported having applied a loxoprofen patch five times after the first discharge for back pain after stopping the oral NSAIDs. This episode, together with the development of nephrotic-range proteinuria following NSAID use on the first admission, led us to suspect a diagnosis of nephrotic-range proteinuria caused by the topical loxoprofen patch. As expected, all of the patient s symptoms, i.e., peripheral edema, anorexia and pruritus, rapidly improved following the discontinuation of the loxoprofen patch. One week after her second admission, -hour urine collection indicated a protein excretion of. g. The serum creatinine level improved immediately after discontinuing the patch, recovering completely two months later (Fig. ). Hence, we made a fi-

4 nal diagnosis of nephrotic-range proteinuria caused by the topical loxoprofen patch. The patient was treated conservatively and advised to avoid NSAIDs in any form in the future. Six months after discharge, she remained edema-free, and her urinary protein excretion was below. g per day. Discussion NSAIDs are widely used to treat a variety of acute and chronic pain conditions, although their usefulness is often limited by serious systemic adverse effects, including dosedependent gastrointestinal disturbances, such as nausea, vomiting and dyspepsia (7, 8). Additionally, the nephrotoxic potential of NSAIDs is well known. This includes acute renal failure, chronic renal injury, nephrotic syndrome and interstitial nephritis, as well as abnormalities of water balance and sodium and potassium homeostasis (). It is believed that sudden-onset proteinuria combined with interstitial nephritis and renal insufficiency, although relatively rare, is a distinct characteristic of NSAID-related syndrome. Although it has not yet been clearly elucidated, the mechanism of this syndrome was first outlined by Brater and Whelton in 999. It is possible that this syndrome may be induced by excessive amounts of vasoactive leukotrienes produced by shunting of the arachidonic acid pathway into the lipoxygenase pathway, owing to cyclooxygenase blockade by NSAIDs, resulting in elevated glomerular permeability (, 9). The present patient initially exhibited bilateral leg edema with nephrotic-range proteinuria, a relatively low serum albumin concentration and progressive renal insufficiency, which are compatible with the clinical findings of the syndrome described above. In terms of the latent period, it is well known that nephrotic-range proteinuria manifests after several days to months of NSAID exposure, with a mean exposure time of. months (). In this case, the symptoms manifested six months after the start of lornoxicam therapy. Therefore, it is highly likely that the patient suffered from NSAID-related renal syndrome. The absence of peripheral eosinophilia, eosinouria, fever and drug rashes was also consistent with a diagnosis of this syndrome (). The rapid resolution of nephrotic syndrome in parallel with the improvement in renal insufficiency following the discontinuation of NSAIDs, as well as the renal biopsy showing MCD associated with interstitial nephritis, confirmed the diagnosis of this type of NSAID-related nephropathy. On the second admission, although an increased level of urine protein excretion was less evident than at the time of the first admission, the recurrence of the same symptoms observed during the previous admission despite the patient s refraining from taking oral NSAIDs and a complete drug history led us to suspect NSAID patch-induced renal toxicity. The immediate remission noted following the withdrawal of the NSAID patch supports this possibility, as has previously been observed with other types of topical NSAID formulations (, ). Although it is possible that the relapse of renal impairment was caused by acute tubular necrosis (ATN) secondary to depression of the renal blood flow resulting from the inhibition of prostaglandin synthesis by the NSAID patch or dehydration due to anorexia, the simultaneous presence of evident proteinuria is not typical of ATN. Moreover, it is known that ATN caused by NSAID therapy is a dose-dependent process (). In the present case, although topical NSAIDs were used on an as needed basis, no oral NSAIDs were used after the first discharge. Therefore, these facts led us to think that the patient s renal impairment was not caused by ATN, but rather by other doseindependent mechanisms. Although topical NSAIDs are widely used due to their presumed safety, little is known regarding the safety of these drugs, especially in older patients (). In terms of nephrotoxicity in particular, there are only a few previous reports of nephrotic syndrome and renal impairment associated with topical NSAID use (, ). Furthermore, to the best of our knowledge, no previous reports have shown an association between the application of topical NSAID patches and the occurrence of nephrotic syndrome associated with interstitial nephritis. Patches containing % loxoprofen sodium hydrate (LSHP) for the treatment of pain associated with osteoarthritis, muscular strain or trauma have been marketed since 6. With multiple topical dosing (once daily), a plasma steady state concentration of loxoprofen of approximately.9 ng/ml is attained within four days of treatment initiation (). In comparison, the maximal concentration (Cmax) and time to maximal concentration (Tmax) of loxoprofen sodium hydrate (LSH) in the plasma when LSH is used orally are. μg/ml and. hours, respectively (). Therefore, it is notable that the maximum plasma concentration of LSH attained with multiple doses of LSHP is much lower than that attained with the oral intake of LSH. These facts and our experience in this case strongly support the possibility that LSH-induced nephrotic syndrome can be caused by a dose-independent mechanism, such as an allergic or immunological reaction. As to the development of nephrotic syndrome due to the oral administration of NSAIDs, most patients with this syndrome exhibit spontaneous remission within one month to one year after drug discontinuation (). Consistent with this finding, in this case, the patient s proteinuria and edema promptly improved and the serum creatinine level recovered completely one month after the discontinuation of LSHP. The clinical course of our patient was very similar to that observed in previously reported cases of nephrotic syndrome and renal impairment caused by piroxicam- () or ibuprofen-containing gel (). Of note, although the Tmax and Cmax for NSAIDs are comparable when the drug is administered via gel or patch, the overall clearance of these drugs is more efficient when administered as a patch versus gel, with a clearance rate more than double with patch administration over a 8-hour period (6). This highlights that NSAID patches are different from NSAID gel, not only in form, but also in pharmacokinetics. Therefore, it is worth noting that

5 NSAID patches can induce nephrotoxicity, as previously reported for NSAID gel. In summary, this case report is, to the best of our knowledge, the first report of nephrotic-range proteinuria and interstitial nephritis caused by topical NSAID patch use. Despite the systemic absorption of these drugs, few previous reports have documented the occurrence of renal toxicity resulting from topical NSAID use. This is partly because the lack of awareness of these potential interactions and spontaneous clinical remission may have resulted in underreporting of this condition. The present case highlights the fact that this syndrome can be induced by dose-independent mechanisms. Our patient s renal impairment and symptoms promptly improved merely by discontinuing the NSAID patch. The authors state that they have no Conflict of Interest(COI). References. Schlondorff D. Renal complications of non steroidal antiinflammatory drugs. Kidney Int : 6-6, 99.. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory drugs. N Engl J Med : 6-7, 98.. Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med 6: S-S, O Callaghan CA, Andrews PA, Ogg CS. Renal disease and topical non-steroidal drug use. Br Med J 8: -, 99.. Andrews PA, Sampson SA. Topical non-steroidal drugs are systemically absorbed and may cause renal disease. Nephrol Dial Transplant : 87-89, Mazières B. Topical ketoprofen patch. Drugs R D 6: 7-,. 7. Heyneman CW, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic diseases: a comparison. Drugs 6: -7,. 8. Brewer AR, McCarberg B, Argoff CE. Update on the use of topical NSAIDs for the treatment of soft tissue and musculoskeletal pain: a review of recent data and current treatment options. Phys Sportsmed 8: 6-7,. 9. Alper AB Jr, Meleg-Smith S, Krane NK. Nephrotic syndrome and interstitial nephritis associated with celocoxib. Am J Kidney Dis : 86-9,.. Abraham PA, Keane WF. Glomerular and interstitial disease induced by nonsteroidal anti-inflammatory drugs. Am J Nephrol : -6, 98.. Markowitz GS, Perazella MA. Drug-induced renal failure: a focus on tubulointerstitial disease. Clin Chim Acta : -7,.. Hadgraft J, Whitefield M, Rosher PH. Skin penetration of topical formulations of ibuprofen %: an in vitro comparative study. Skin Pharmacol Appl Skin Physiol 6: 7-,.. Sugawara S, Hasegawa S, Naganuma H, Matsuzawa T. Pharmacokinetics study of the hydrogel patch containing loxoprofen sodium (LX-A) following days applications repeated once or twice a day. Rinshou Iyaku (Journal of Clinical Therapeutics & Medicines) : 79-9, 6 (in Japanese, Abstract in English).. Naganuma H, Mochizuki Y, Kawahara Y. Study of pharmacokinetics following oral administration of loxoprofen sodium (CS-6) in humans. Rinshou Iyaku (Journal of Clinical Therapeutics & Medicines) : 9-6, 986 (in Japanese, Abstract in English). The Japanese Society of Internal Medicine