Ciprofloxacin-Induced Acute Interstitial Nephritis and Autoimmune Hemolytic Anemia

Abstract

Ciprofloxacin has been associated with several side effects including interstitial nephritis and hemolytic anemia. The combination of both side effects is extremely rare. In this report, we describe a case of ciprofloxacin-induced interstitial nephritis and autoimmune hemolytic anemia. Hemolytic anemia improved after stopping the drug and initiation of steroid therapy. Unfortunately, acute interstitial nephritis was irreversible and the patient developed end-stage renal disease.

• Ciprofloxacin
• Interstitial nephritis
• Hemolytic anemia

Introduction

Ciprofloxacin is widely used in practice due to its broad-spectrum antibacterial activity. Adverse effects due to ciprofloxacin are rare and typically affecting the gastrointestinal tract and central nervous system.[[1]] Acute interstitial nephritis (AIN) is a well-known complication of ciprofloxacin.[[2]], [[3]], [[4]] Ciprofloxacin has also been associated with intravascular hemolysis, which can be due to either glucose-6-phosphate dehydrogenase (G6PD) deficiency or autoimmune mediated hemolytic anemia.[[5]], [[6]], [[7]] The combination of AIN and intravascular hemolysis due to ciprofloxacin is extremely rare. Ciprofloxacin induced AIN and hemolysis due to G6PD deficiency has only been reported once.[[8]] We could not find any case report of AIN and autoimmune hemolytic anemia associated with ciprofloxacin treatment in the literature.

Case Report

A 79-year-old white male with no significant past medical history was admitted to outside hospital with history of fever, generalized malaise, and weakness. During his hospital stay, he developed a macular papular rash on his chest, back and arms after treatment with intravenous ciprofloxacin for urinary tract infection. He never received fluoroquinolone antibiotics in the past. The drug was stopped immediately. His laboratory studies during his hospital stay were unremarkable with normal serum electrolytes, and hemoglobin. His serum creatinine was 1.1 mg/dL. Urinalysis revealed 3–5 white blood cells (WBC) and red blood cells (RBC) per high power field with no protein. The patient was discharged home after one week. Two days later, the patient was admitted to another outside hospital because of jaundice, generalized weakness, nausea, and vomiting. Laboratory studies showed a WBC of 13,500/mm³ with 12.4% eosinophils, hemoglobin 7.6 g/dL, platelet count 117,000/mm³, LDH 676 U/L, total bilirubin 5.0 mg/dL, indirect bilirubin 3.8 mg/dL, blood urea nitrogen (BUN) 79 mg/dL, and creatinine 3.0 mg/dL. Urinalysis was negative for hemoglobin and eosinophils. The patient became oligoanuric upon admission. Renal ultrasound revealed no hydronephrosis. Endoscopic retrograde cholangiopancreatography showed some sludge with gallstones but no true obstruction of common bile duct. In the next two days, his hemoglobin dropped to 5.1 g/dL and his BUN and serum creatinine increased to 171 mg/dL and 9.8 mg/dL respectively. Peripheral smear did not show any schistocytes. Blood transfusion was held due to difficulty with crossmatch. The patient was treated with prednisone 60 mg daily. Due to deterioration of renal function and severe anemia, the patient was subsequently transferred to University of Arkansas for Medical Sciences.

Physical examination on admission revealed a well-developed white man weighing 78 kg. Lying supine, he had a pulse of 72 beats/min with a blood pressure of 135/75 mm Hg. There was no jaundice or skin rash. His lungs were clear. Other physical examination was essentially unremarkable. Laboratory studies at this time revealed: WBC, 16,900/mm³; differential count, 89% neutrophils, 0.3% eosinophils; hemoglobin 4.8 g/dL; reticulocyte count, 5.95%; platelet count, 134,000/mm³; BUN, 111 mg/dL; creatinine, 7.2 mg/dL; total bilirubin, 1.1 mg/dL; LDH, 676 U/L; C3, 26.3 mg/dL (normal 50–100); C4, 7.4 mg/dL (normal 12.5–45); haptoglobin, 11 mg/dL (normal 75–350); fibrinogen, 199 mg/dL; D-Dimer 2.2 µg/mL (normal 0–0.5); urinalysis, +++ blood, ++ protein, no dysmorphic RBC or RBC casts, no urine eosinophils. There were no abnormalities in serum electrolytes, prothrombin time, partial thromboplastin time, liver function test, and serum protein electrophoresis. Tests for antinuclear antibody, rheumatoid factor, cold agglutinins, urine hemoglobin, serologic studies for hepatitis A, B, C and ehrlichiosis, blood and urine culture were negative.

Upon admission, the patient was started on hemodialysis and methylprednisolone 125 mg every 8 h. Peripheral blood smear revealed schistocytes. The direct antiglobulin (coombs) test was positive for IgG and complement. The patient was transfused with three units of packed red blood cell. A kidney biopsy was performed, which revealed extensive diffuse interstitial lymphocytic infiltrates with accompanying interstitial edema and tubular destructions. The diagnosis of autoimmune hemolytic anemia and AIN associated with ciprofloxacin was made. His hemoglobin remained stable during his hospital stay. The patient was discharged a week after admission on prednisone 60 mg once a day. The patient remained dialysis dependent after discharge.

Discussion

In the original reports of methicillin associated AIN, the onset of renal dysfunction typically occurred after 8 to 20 days of drug therapy.[[9]] The clinical presentation of ciprofloxacin-induced AIN include non-oliguric renal failure, fever, rash, myalgias, azotemia, eosinophilia, and eosinophiluria.[[2]], [[4]] Urinalysis may display a sterile pyuria, leukocyte casts, hematuria, and eosinophiluria. The presence of eosinophilia and eosinophiluria support the diagnosis of AIN; however, their absences do not exclude it.[[10]] As this case demonstrated, eosinophiluria was negative. Eosinophiluria was found to have a sensitivity of 40%, specificity of 72% and positive predictive value of only 38% in diagnosing AIN.[[11]] The definitive diagnosis depends on demonstration of the histopathologic changes compatible with AIN. However, the majority of patients with AIN do not require renal biopsy. If patients fail to improve after drug discontinuation and immunosuppressive therapy is contemplated, a renal biopsy is recommended.[[12]] Biopsy was done in our case to rule out other diseases associated with hemolytic anemia and acute renal failure such as hemolytic uremic syndrome and hemoglobinuria. Kidney biopsy result showed no proliferation or segmental sclerosis in the glomeruli. There was a moderate chronic inflammatory cell infiltrate involving 40–50% of the interstitium with accompanying edema. The infiltrate was composed of lymphocytes, plasma cells, and eosinophils. The tubules showed flattening of the lining epithelium and focal loss of brush border. There was no evidence of pigment-induced acute tubular necrosis. The blood vessels showed focal intimal fibrosis but no vasculitis or thombotic microangiopathy. Immunofluorescence and electron microscopy were also negative. The renal biopsy diagnoses were acute interstitial nephritis and arteriosclerosis.

Initial management of drug-induced AIN is the removal of the causative agent. Steroids therapy has been advocated for those cases requiring hemodialysis or for prolonged renal insufficiency.[[13]], [[14]] However, evidence supporting steroids is largely anecdotal.[[15]] In our case steroids was given because of prolonged renal failure requiring hemodialysis and the associated autoimmune hemolytic anemia. To date there is no large randomized controlled trial assessing the efficacy of steroids or other immunosuppressive therapy in AIN.

Quinolone antibiotics such as nalidixic acid and ciprofloxacin have been associated with intravascular hemolysis.[[5]], [[6]], [[7]], [[16]], [[17]] Some of the patients with ciprofloxacin-induced hemolytic anemia have G6PD deficiency.[[6]], [[8]] The enzyme catalyzes the first step in the pentose phosphate pathway. The amount of hemolysis and the severity of constitutional symptoms depend upon the severity of the enzyme defect and upon the degree of oxidant stress.[[18]] Other case with ciprofloxacin-induced hemolytic anemia is probably immune mediated.[[5]] The direct antiglobulin test in our case was positive for IgG and complement, which suggest that the etiology is likely immune-mediated. In drug-induced autoimmune hemolytic anemia, withdrawal of the drug and steroids may be indicated for short periods of time in patients with severe anemia.[[19]] This is the first case report on ciprofloxacin-induced AIN and coombs-postive autoimmune hemolytic anemia.