A 42-year old patient was referred by her primary care physician with new onset azotemia – over a 2-week period her serum creatinine had increased from 0.9 mg/dL to 1.96 mg/dL; she was otherwise asymptomatic. One week prior to presentation, she had been seen by her PCP for a new-onset cough and yellow-tinged sputum and was empirically started on a 5-day course of levofloxacin (Levaquin).
 |
William Thomas Councilman
(1854-1933)
|
At the time of referral, the patient denied itching or rash. Physical examination was unremarkable. Her laboratory data showed the following: Urinalysis: specific gravity 1.015, pH 5.0, trace to 1+ albumin, 1+ leukocytes, and trace blood. Urine sediment showed several white blood cells, one nondysmorphic red blood cell, 3 renal tubular epithelial cells/HPF; there was one degenerating cellular cast that was suspicious for a white blood cast. Her complete blood count was normal with no eosinophilia. Her BUN was 46 mg/dL, serum creatinine 2.2 mg/dL, and she had normal electrolytes. Renal ultrasound revealed bilateral echogenic kidneys that were of normal size.
A diagnosis of levofloxacin-induced acute interstitial nephritis (AIN) was made and the antibiotic was discontinued. 1 week after discontinuation of the levofloxacin, her serum creatinine returned to her baseline of 0.9 mg/dL.
Discussion: Dr. Connie Rhee and Dr. Li-Li Hsiao A diagnosis of levofloxacin-induced acute interstitial nephritis (AIN) was made and the antibiotic was discontinued. 1 week after discontinuation of the levofloxacin, her serum creatinine returned to her baseline of 0.9 mg/dL.
 |
| Dr. Connie Rhee |
Dr. Connie Rhee is a 3rd-year Clinical Research Fellow in the Joint Brigham and Women’s-Massachusetts General Hospital Nephrology Fellowship Training Program. She completed medical school at the Northwestern University Feinberg School of Medicine and residency at the Oregon Health and Science University Harvard Medical School
Acute Interstitial Nephritis: Pathology Pentad AIN
Acute Interstitial Nephritis: Pathology Pentad AIN
“An acute inflammation of the kidney characterized by cellular and fluid exudation in the interstitial tissue, accompanied by, but not dependent on, degeneration of the epithelium; the exudation is not purulent in character, and the lesions may be both diffuse and focal.” –W.T. Councilman, MD, The Journal of Experimental Medicine, July-Sept 1898.
 |
| Dr. Li-Li-Hsiao |
The etiologies of acute interstitial nephritis (AIN) have expanded since Councilman’s original description a century ago, but the pathologic findings remain unchanged (1). AIN, noted in 15-27% of biopsies for acute kidney injury (AKI) (2,3) is recognized by its hallmark 1) inflammatory interstitial infiltrate of lymphocytes and monocytes (fewer eosinophils, plasma cells, and neutrophils), 2) interstitial edema, 3) renal tubule separation, 4) tubulitis, 5) and absence of glomerular or vascular pathology (4-6).
Evolution of Drug-Induced AIN
In the pre-antibiotic era, most AIN observations were attributed to infections (6,7). An expanding list of medications now accounts for 70% of cases (8) and the clinical presentation of AIN has become heterogeneous. Whereas methicillin-associated AIN was frequently associated with the “hypersensitivity triad” of fever, rash, and eosinophilia in the 1960’s-70’s, contemporary AIN culprits now include non-beta-lactams which have a lower frequency of hypersensitivity symptoms. PPI-induced AIN was first recognized in 1992 (9) and like NSAID-induced AIN (10) is associated with less hypersensitivity (10% with triad (11)) and a later onset (11 weeks in one series (12)) in comparison to beta-lactams. These three medication classes account for the majority of cases in the largest retrospective treatment studies (13,14), but they are a miniscule tip of the drug-induced AIN iceberg.
Laboratory findings
The urinalysis: white blood cells and casts are often noted on urine sediment but absence does not exclude AIN (15); Urine-albumin-to-creatinine ratio (UACR): proteinuria is mild (<1-1.5g/day) but can be nephrotic in NSAID-induced AIN associated with minimal change or membranous disease (15,16). Renal biopsy remains the definitive diagnostic modality, as other tests (e.g. gallium scanning, eosinophiluria) have limited sensitivity and specificity (15).
Treatment
AIN’s presentation, particularly with drugs and infections, points to an immunologic pathogenesis, as evidenced by 1) extrarenal hypersensitivity symptoms, 2) absence of dose-dependency, 3) recurrence with re-exposure and 4) incidence in a small proportion of patients (16). Studies suggest a major role for a cell-mediated immune reaction on the basis of 1) T-cell lymphocytic predominance in infiltrates, 2) negative immunofluorescence, and 3) granulomatous infiltrates indicative of a delayed-type hypersensitivity reaction (16).
If renal function fails improve within 5-7 days of discontinuation of the causative agent, treatment may be pursued (either empiric, or following renal biopsy) which usually entails steroid therapy (either a 3-day pulse of 500 mg to 1 g/day intravenous methylprednisone or treatment with oral prednisone (1 mg/Kg)). There are no prospective randomized controlled trials to date to assess the efficacy of steroids in treatment. The two largest observational studies have demonstrated conflicting results. In Clarkson et al’s study (13) of 60 patients with biopsy-proven AIN (92% drug-induced), patients receiving steroids vs. conservative management had no statistically significant difference in renal function at 1, 6, and 12-months follow-up. Median time interval from symptom onset to biopsy was 3.5 weeks; thus, given that interstitial fibrosis may develop within 7 days of AIN onset and portends worse prognosis, the role of steroids may have been limited at this stage of disease. Subsequently, Gonzalez et al (14) demonstrated a significant improvement in renal function among 52 patients receiving steroids in a multicenter study of 61 patients with drug-induced AIN. Further analysis of the steroid group demonstrated that patients with complete vs. incomplete renal recovery had significantly shorter intervals between drug discontinuation and biopsy, reduced severity of interstitial fibrosis, and shorter intervals between drug discontinuation and steroid initiation (mean±SD: 13±10 vs. 34±17 days, p<0.0001). For steroid-unresponsive, dependent, or intolerant cases, there has been anecdotal success with MMF and cyclosporine (17,18).
Chronic Interstitial Nephritis Pathology
AIN’s more indolent counterpart, chronic interstitial nephritis (CIN), has a diverse spectrum of etiologies, yet maintains a fairly homogenous pathologic pattern, notable for 1) interstitial fibrosis causing tubule separation, 2) a less pronounced inflammatory interstitial infiltrate, and 3) tubular cell atrophy and/or dilation (7,19,20).
Herbal Nephrotoxins
An under-recognized cause of CIN is herbal medications, consumed by 75% of the world’s population, largely in underdeveloped countries (21). There is also a high prevalence of utilization in industrialized countries such as the US
The nephrotoxicity of herbal products gained recognition in the 1990’s when > 100 Belgian women taking weight-loss pills were diagnosed with a rapidly progressive interstitial fibrosis following the manufacturer’s substitution of the Chinese herbal ingredient, Aristolochic Acid (AA), for Stephania Tetrandra. Over 70% of cases progressed to ESRD, and 40-45% patients developed transitional cell carcinomas. Cases of AA nephropathy have been reported in the US , UK , France Germany, Spain , China , Taiwan , Korea , and Japan
Despite the FDA’s recommendations that all AA products be discarded, there have been subsequent reports of products sold online (24). AA is one of many botanicals resulting in CIN, and the nephrotoxicity of many supplements remains unknown. Under the 1994 Dietary Supplement Health and Education Act, manufacturers of supplements (herbals/ botanicals, minerals, vitamins, amino acids) are not required to register their products with the FDA or obtain FDA approval (25). In the absence of safety, efficacy, and labeling regulations, consumers of supplements are at risk for nephrotoxicity due to 1) contamination, 2) ingredient substitution, 3) drug interactions, and 4) inadequate knowledge.
In conclusion, drugs are a common cause of AIN, and our clinical suspicion for drug-induced nephrotoxicity should be high, as delayed intervention results in poor renal outcomes. Given that the nephrotoxicity of many herbal (and conventional) medicines is unknown, we should encourage more research and education in this area and advocate for the same regulation of herbal medications as applied to conventional medications.
References
1. Councilman WT. Acute Interstitial Nephritis. The Journal of experimental medicine 1898;3:393-420.
2. Farrington K, Levison DA, Greenwood
3. Haas M, Spargo BH, Wit EJ, Meehan SM. Etiologies and outcome of acute renal insufficiency in older adults: a renal biopsy study of 259 cases. American journal of kidney diseases : the official journal of the National Kidney Foundation 2000;35:433-47.
4. Grad YH, Seifter JL, Levy BD, Loscalzo J. Clinical problem-solving. Bitter pills. The New England journal of medicine 2010;363:1847-51.
5. Perazella MA, Markowitz GS. Drug-induced acute interstitial nephritis. Nature reviews Nephrology 2010;6:461-70.
6. Rossert J, Fischer E. Acute Interstitial Nephritis. In: Floege J JR, Feehally J, ed. Comprehensive Clinical Nephrology. 4th ed. St. Louis , MO
7. Meyers CM. Acute and Chronic Tubulointerstitial Disease. In: Greenberg A CA, Coffman TM, Falk RJ, Jennette JC, ed. Primer on Kidney Diseases. 5th ed. Philadelphia , PA
8. Baker RJ, Pusey CD. The changing profile of acute tubulointerstitial nephritis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 2004;19:8-11.
9. Ruffenach SJ, Siskind MS, Lien YH. Acute interstitial nephritis due to omeprazole. The American journal of medicine 1992;93:472-3.
10. Pirani CL, Valeri A, D'Agati V, Appel GB. Renal toxicity of nonsteroidal anti-inflammatory drugs. Contributions to nephrology 1987;55:159-75.
11. Brewster UC, Perazella MA. Proton pump inhibitors and the kidney: critical review. Clinical nephrology 2007;68:65-72.
12. Geevasinga N, Coleman PL, Webster AC, Roger SD. Proton pump inhibitors and acute interstitial nephritis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2006;4:597-604.
13. Clarkson MR, Giblin L, O'Connell FP, et al. Acute interstitial nephritis: clinical features and response to corticosteroid therapy. Nephrology, dialysis, transplantation : official publication of the European
14. Gonzalez E, Gutierrez E, Galeano C, et al. Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis. Kidney international 2008;73:940-6.
15. Michel DM, Kelly CJ. Acute interstitial nephritis. Journal of the American Society of Nephrology : JASN 1998;9:506-15.
16. Rossert J. Drug-induced acute interstitial nephritis. Kidney international 2001;60:804-17.
17. Preddie DC, Markowitz GS, Radhakrishnan J, et al. Mycophenolate mofetil for the treatment of interstitial nephritis. Clinical journal of the American Society of Nephrology : CJASN 2006;1:718-22.
18. Zuliani E, Zwahlen H, Gilliet F, Marone C. Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following cyclosporine treatment. Clinical nephrology 2005;64:155-8.
19. Nangaku M FT. Chronic Interstitial Nephritis. In: Floege J JR, Feehally J, ed. Comprehensive Clinical Nephrology. 4th ed. St. Louis , MO
20. Braden GL, O'Shea MH, Mulhern JG. Tubulointerstitial diseases. American journal of kidney diseases : the official journal of the National Kidney Foundation 2005;46:560-72.
21. Isnard Bagnis C, Deray G, Baumelou A, Le Quintrec M, Vanherweghem JL. Herbs and the kidney. American journal of kidney diseases : the official journal of the National Kidney Foundation 2004;44:1-11.
22. Tindle HA, Davis RB, Phillips RS, Eisenberg DM. Trends in use of complementary and alternative medicine by US adults: 1997-2002. Alternative therapies in health and medicine 2005;11:42-9.
23. Debelle FD, Vanherweghem JL, Nortier JL. Aristolochic acid nephropathy: a worldwide problem. Kidney international 2008;74:158-69.
24. Gold LS, Slone TH. Aristolochic acid, an herbal carcinogen, sold on the Web after FDA alert. The New England journal of medicine 2003;349:1576-7.
25. US Food and Drug Administration: Dietary Supplements. (Accessed at http://www.fda.gov/food/dietarysupplements/default.htm.)
