Sitagliptin Caused Acute Drug Induced Interstitial Nephritis
ABSTRACT: Drug-induced acute interstitial nephritis (AIN) is a recognized cause of acute and chronic renal injury. In this first case of pathology-confirmed, sitagliptin-induced AIN in a 69-year-old male, the patient has history of type 2 diabetes mellitus and was started on sitagliptin 4 weeks before the onset of renal failure. The usual etiologies for acute kidney injury were not immediately evident in this case. Prescribing physicians should be aware of the possibility that sitagliptin may induce AIN and renal failure, and how steroids may help speed recovery.
A 69-year-old male was admitted to the emergency department because of microscopic hematuria identified in the primary care physician’s office, associated with urinary urgency and frequency. These symptoms were progressively worsening for 2 days. The patient had been well until 2 days before this presentation.
The patient complained of chills and night sweats, but denied having any fever or arthralgia. His appetite was fair. He reported recently starting sitagliptin 4 weeks prior to this emergency department visit. He denies any other new prescribed medications or the use of any over-the-counter medication (eg, ibuprofen). Because the patient had a history of nephrolithiasis, an abdominal CT without contrast was performed in the emergency department, which demonstrated mild left perinephric soft tissue stranding—indicating pyelonephritis, but with no evidence of nephrolithiasis.
The patient’s past medical history includes hypertension, dyslipidemia, coronary artery disease with congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus type 2, and nephrolithiasis. He also has a history of acute kidney injury secondary to using a medication during his right knee surgery roughly 30 years ago. Renal failure has resolved, but he was unable to recall the name of the medication. The patient has allergies to metformin, which causes diarrhea, and varenicline, which causes depression.
The patient smokes 1 pack-per-day, drinks alcohol occasionally, and does not use illicit drugs. His mother is alive with coronary artery disease, but his father is deceased secondary to a brain aneurysm. There is no family history of kidney disease.
Physical Examination
On physical examination, the temperature was 98.3°F, blood pressure was 140/69 mm Hg, and the pulse was 88 beats per minute with normal sinus rhythm and no evidence of murmur. Lungs were clear to auscultation, with only mild tenderness in the right upper and lower quadrant areas. Bilateral costovertebral angles have no tenderness. The abdomen had no guarding and no rebound tenderness. There were no skin rashes, no joint swelling, and no tenderness on palpation of joints.
Laboratory Tests
The laboratory tests upon admission were as follows: complete blood count with differential, blood glucose level, total albumin, globulin, and liver function tests were normal. There was no eosinophilia. However, carbon dioxide was 21 mEq/L, blood urea nitrate (BUN) level was 54 mg/dL, creatinine (cr) was 4.95 mg/dL, and estimated glomerular filtration rate (eGFR) was 12 mL/min/1.73 m2.
Four months prior to hospitalization, BUN was 15 mg/dL, creatinine was 1.07 mg/dL, and eGFR was 69 mL/min/1.73 m2. Urine analysis was hazy with a pH of 6.0, specific gravity 1.009, protein 30 mg/g (high), glucose 100 mg/dl, ketone negative, occult blood small amount, nitrite negative, bilirubin negative, leukocyte esterase negative, red blood count of 1 hpf, white blood count of 4 hpf, and 8 granular casts. A blood culture was performed which was sterile.
Medication
The patient was taking the following medications at home: amlodipine/valsartan 10/320 mg 1 tablet PO daily, clobetasol 1 application topically twice daily, hydroxyzine 25 mg PO 3 times daily as needed for anxiety, Flonase 2 sprays to each nostril daily, sitagliptin 100 mg 1 tablet PO daily, gemfibrozil 600 mg 1 tablet PO daily, omeprazole 20 mg 1 tablet PO daily, glipizide 10 mg 1 tablet PO twice daily, cetirizine 10 mg 1 PO daily, and aspirin 81 mg 1 tablet PO daily.
Figure 1. Lymphocyte and eosinophil-rich interstitial infiltrate with associated tubular epithelial cell damage.
Hospital Treatment
The patient was admitted because of acute kidney injury. Broad-spectrum antibiotics were started initially because of the possibility of having a urinary tract infection or mild pyelonephritis, which was indicated by the symptoms of microscopic hematuria, dysuria, urgency, as well as right upper and lower abdominal pain. However, urine cultures and blood culture came back negative, bilateral renal ultrasound did not show any abnormality, and the patient had good urine output, as post-voiding limits. Urinary tract infection, pyelonephritis, and obstructive uropathy were ruled out.
Other laboratory tests results included: 24 hours urine volume 3000 mL, creatinine 24-hours at 1.34 mg/dL, albumin at 20 mg/24 hours, total protein 1770 g/dL, protein/creatinine ratio 1317 mg/g, alpha-1 globulin at 9%, alpha-2 globulin at 33%, beta globulin at 22%, gamma globulin at 15%, and urine protein electrophoresis showing no abnormal peaks detected. Serum cryoglobulins, antinuclear antibody, antiproteinase-3, anti-myeloperoxidase, double strand DNA antibody, and GBM antibody all came back negative. C3 was 165 mg/dL (high), C4 was 35.6 mg/dL, and total complement (CH50) >60 U/mL (high). Hepatitis panel was negative, HIV 1 & 2 antigen and antibody were negative, anti-streptolysin was 47 units/mL, which was within normal limits, and antineutrophil cytoplasmic antibodies level was negative.
During the hospital stay, eGFR continuously declined. The most extreme BUN was 67 mg/dL, creatinine was 6.28 mg/dL, and eGFR was 9 mL/min/1.73 m2 on the 5th day of admission. A right internal jugular vein temporary dialysis catheter was placed for hemodialysis because of the worsening renal function and a renal biopsy was performed the same day. The patient was suspected of having a sitagliptin-induced acute kidney injury; the sitagliptin was subsequently discontinued upon admission.
Renal biopsy demonstrated an acute interstitial nephritis (AIN) characterized by interstitial edema and a diffuse mononuclear interstitial infiltrate with numerous eosinophils (Figure 1). Associated tubular epithelial cell damage was present, characterized by nucleomegaly and cytoplasmic basophilia. Immunohistochemical staining showed the mononuclear cells to be predominantly CD3-positive T lymphocytes (Figure 2), as expected in a hypersensitivity-type AIN. There were only sparse CD20-positive B lymphocytes, with polyclonal kappa and lambda light chain staining. There was no granulomatous inflammation.
Other intrarenal etiologies for acute kidney injury such as acute glomerulonephritis, ischemic acute tubular necrosis, vasculitis, thrombotic microangiopathy, cholesterol embolization, and cast nephropathy were all ruled out by the absence of specific morphologic findings. Immunofluorescence studies and electron microscopy further failed to demonstrate evidence of an immune complex-related etiology. There was mild arteriolar hyalinosis, consistent with the history of hypertension as well as diabetes, however there was no evidence of diabetic glomerulopathy or other chronic renal disease. There was no significant interstitial fibrosis or tubular atrophy.
The patient was discharged home because of improving eGFR on the 7th day of admission.
Figure 2. Predominantly T lymphocyte population.
Follow-Up
Four days after discharging, the patient was readmitted to the same hospital because of recurrent chills and mild fever starting late in the night prior to admission. The patient was not diaphoretic and the patient was given intravenous antibiotics in the emergency room. Patient was found with mild worsening renal function compared to the eGFR when he was discharged. The patient had no dysuria, no hematuria, and still had excellent urine output. At that time, the results of the kidney biopsy confirmed acute kidney injury originated from AIN likely because of the recent medication of sitagliptin.
The patient was then continued on hemodialysis 3 times per week and prednisone 60 mg a day was initiated with a tapering dose. At the same time, 2 sets of blood cultures were sent again, which were negative.
In the office follow-up visit, renal funtion mildly fluctuated but generally continued improving. Three weeks after starting tapering doses of prednisone, his BUN was 36 mg/dL, creatinine was 1.56 mg/dL and eGFR was 44 mL/min/1.73 m2.
Discussion
AIN is considered one of the major causes of reversible acute kidney injury. Drugs are the most common cause of AIN. The true incidence of drug-induced AIN is unknown and probably large numbers of cases remain unrecognized with mild elevations in renal dysfunction.1 Various drugs can induce AIN; NSAIDs are most frequently the cause among drugs.
Over the last 3 to 4 decades, there has been a changing profile of associated medications. In the 1970s and 1980s, most cases were penicillin-related and associated with typical hypersensitivity symptoms. In the 1990s, etiology became more diverse and there were less associated symptoms.2 However, omeprazole has become a common cause of AIN since 1990s.3,4
Diagnosis. The clinical presentation and laboratory findings vary according to the class of drug involved. A definitive diagnosis of AIN can only be established by kidney biopsy. Sometimes diagnosis of drug-induced AIN is made on the basis of clinical presentation and not confirmed with histology. Noninvasive tests, such as gallium scintigraphy and testing for eosinophiluria, are of limited diagnostic utility and may lead to the possibility of an inaccurate diagnosis.
Treatment. The mainstay of therapy for drug-induced AIN is timely discontinuation of the causative agent. Corticosteroid therapy appears to have a positive effect in some patients with drug-induced AIN, especially when treatment is initiated early in the course of the disease.5 A recent study provides more evidence that steroid treatment has a greater degree of improvement in renal function.2
Sitaglipin is a widely used oral glucose-lowering medication that acts via the incretin-hormone system. Recent reports demonstrate that the use of sitaglipin generally has not been associated with any appreciable excess risk of all-cause hospital admission or all-cause mortality in a broad-spectrum of patients.6 However, high-dose sitaglipin was reported to cause acute kidney injury and rhabdomyolysis from combination of sitagliptin and simvastatin.7 There are also reports of the use of sitagliptin associated with AIN.8 Unfortunately, in this report, no kidney biopsy was performed to confirm drug-induced pathology changes.
Outcome of the case. In this case, the presentation is not classic. There was no history of skin rash, arthralgia, or eosinophilia. Instead, the case presented with hematuria, flank pain, and possible sepsis, which were eventually ruled out.
A temporal relation between AIN, causing renal failure, and exposure to the sitagliptin was suspected upon admission. The offensive medication was discontinued. The patient was started on steroids after the pathology report, and renal function was greatly improved in the following 1 month. Patient has been on omeprazole for at least 5 years prior to this episode of acute kidney injury. Omeprazole has been continued during and after the onset of AIN. Therefore, there is not any tempospacial evidence of omeprazole as a medication which could have caused the AIN in this case.
The data suggests that the abovementioned presentation of sitagliptin-causing AIN can be very atypical, but possible. New evidence supports that steroid treatment results in improvement in renal function, and that it is reasonable to start steroids for the treatment of drug-induced AIN when the result of final kidney biopsy is not available. ■
References:
1. Perazella MA, Markowitz GS. Drug-induced acute interstitial nephritis. Nat Rev Nephrol. 2010;6(8):461-470.
2. Raza MN, Hadid M, Keen CE, et al. Acutetubulointerstitialnephritis, treatment with steroid and impact on renal outcomes. Nephrology (Carlton). 2012;17(8):748-753.
3. Simpson IJ, Marshall MR, Pilmore H, et al. Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases. Nephrology (Carlton). 2006;11(5):381-385.
4. Myers RP, McLaughlin K, Hollomby DJ. Acute interstitial nephritis due to omeprazole. Am J Gastroenterol. 2001;96(12):3428-3431.
5. Praga M, Gonzalez E. Acute interstitial nephritis. Kidney International. 2010;77:956-961.
6. Eurich DT, Simpson S, Senthilselyan A, et al. Comparative safety and effectiveness of Sitagliptin in patients with type 2 diabetes: retrospective population based cohort study. BMJ. 2013;346:f2667.
7. Kao DP, Kohrt HE, Kugler J. Renal failure and rhabdomyolysis associated with sitagliptin and simvastatin use. Diabet Med. 2008;25:1229-1230.
8. Quasem M, Liu Y. Acute interstitial nephritis associated with sitagliptin use. Am. J Kidney Dis. 2011;57:A81.
Daniel Yanfeng Lin, MD, PhD, isa hospitalist in Summit Health, Chambersburg, PA. He completed his post doctor research fellowship in nephrology in 2004 at Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, MA.
David Hoffman, DO, is the vice president of Summit Health, Pennsylvania and has practiced hospital medicine for more than 10 years.
Vikas Venkat Pulivarti, MD, is a medical graduate of the University of St. Eustatius School of Medicine and is currently doing an observership with Franklin County Medical Associates in Chambersburg, PA.
Catherine S. Abendroth, MD, is a professor of pathology, chief of anatomic pathology, and director of the Renal Pathology Unit at the Penn State Milton S. Hershey Medical Center in Hershey, PA.
Bapurao Pulivarti, MD, is a practicing nephrologist at Franklin County Medical Associates in Chambersburg, PA.