Sulfasalazine-induced nephrotic syndrome in a patient with ulcerative colitis

To the Editor: Sulfasalazine and 5-aminosalicylate (5-ASA) have been used for the treatment of inflammatory bowel diseases (IBD) for decades. Nephrotic syndrome related to aminosalicylate use occurs extremely rarely, and there are only a few case reports, which reveal the causative role of sulfasalazine in the development of nephrotic syndrome. We report a case of nephrotic syndrome induced by sulfasalazine, which improved rapidly after the administration of low-dose corticosteroid therapy and stopping sulfasalazine. A 50-year-old male patient with a 1-year medical history of pancolitis, with a maintenance therapy of sulfasalazine 1000 mg twice daily, presented to our department with a 1.5-week history suggestive of nephrotic syndrome. Previously there was no proven renal disorder. He developed edema affecting the extremities and the eyelids, and complained of dyspnea and a weight gain of 6 kg. His past medical history included adequately controlled hypertension and several orthopedic surgeries. His colitis remained in remission at the time of the admission. Physical examination showed no abnormalities except the swollen extremities and eyelids. His heart rate and blood pressure were 86 beats/min and 140/95 mmHg, respectively. Laboratory findings showed hypoproteinemia with total protein level of 45 g/L and albumin of 16 g/L, hypercholesterolemia with serum cholesterol of 10.53 mmol/L, an elevated erythrocyte sedimentation rate of 81 mm/h, and C-reactive protein level of 49.1 mg/L. A significant proteinuria of 10.56 g/day was noted. Serum urea and creatinine level remained in the normal range. Serological examinations did not demonstrate circulating organ-specific autoantibodies. Serum complement 3 and 4 were within the normal range. Renal ultrasonography and Doppler disclosed no abnormalities. A renal biopsy was performed. On light microscopy, 2 globally sclerosed glomeruli and 15 glomeruli with opened tufts were noted. The opened glomeruli did not reveal alterations. Mild hyaline arteriolosclerosis, interstitial fibrosis and tubular atrophy in 10%–15% of the renal cortex, and hyaline lipid droplets in tubular epithelial cells were encountered. Immunofluorescence microscopy showed no evidence of immunocomplex deposition. Electromicroscopic examination revealed the fusion of foot processes in 60%–70% of podocytes, focal microvillous transformation of podocyte cell bodies, and segmental thinning of the glomerular basement membrane. In conclusion, the morphologic findings were consistent with minimal change nephropathy, induced probably by sulfasalazine. Having the diagnosis of nephrotic syndrome, the administration of sulfasalazine was discontinued and oral methylprednisolone therapy of 1 mg/kg was introduced, resulting in a rapid improvement. One week after starting steroid therapy his edema disappeared, proteinuria resolved, and the other laboratory parameters also began to normalize. He remained completely asymptomatic after discontinuing methylprednisolone treatment. Sulfasalazine has shown efficacy in inducing and maintaining remission in mild-to-moderate ulcerative colitis (UC) since the 1940s. Sulfapyridine moiety is thought to be responsible for most of the side effects of sulfasalazine treatment, which can be managed by dose adjustment in the majority of the cases.1 Despite renal complications of aminosalicylate therapy being infrequent,2 a large British study found an increased risk of renal disease among IBD patients using aminosalicylates.3 Comparing the adverse effects of sulfasalazine and mesalazine, interstitial nephritis was reported to be caused only by mesalazine.2 Since aminosalicylate has structural similarities to salicylates and phenacetin, which are known to cause interstitial nephritis and papillary necrosis, it is not surprising that mesalazine is associated with renal damage, especially interstitial nephritis.4 Minimal change nephropathy related to aminosalicylate use has been reported in only a few cases and mainly in active IBD.5,6 After reviewing the literature, the frequency of sulfasalazine-induced nephrotic syndrome is estimated to be extremely rare.6,7 Histological diagnosis of these cases revealed minimal change nephropathy. In our case, rapid improvement achieved by discontinuing sulfasalazine and administrating low-dose corticosteroid, the asymptomatic state following the discontinuation of steroid, and the earlier case reports confirmed our suspected diagnosis of sulfasalazine-related nephrotic syndrome. How sulfasalazine produces minimal change nephropathy is unknown. Reversible toxicity directed toward the podocytes may be a key player in the pathogenesis. Although IBD itself proved to predispose to renal disease, our case highlights the importance of monitoring renal function and proteinuria in IBD patients treated with aminosalicylate preparations in order to avoid the development of renal complications.