Acute interstitial nephritis Department of nephrology R3 김슬기/prof 이태원

INTRODUCTION  ‘Cellular and fluid exudation in the interstitial tissue...’ Councilman in 1898 kidneys of patients dying of scarlet fever and diptheria organs were sterile  allergic-type phenomenon Incidence Asymptomatic Finnish army recruits : hematuria or proteinuria (+)  0.7 per 100 000 Pettersson E et al. Clin Nephrol 1984; 22:217–222 109 patients from a large centre : unexplained renal impairment with normal sized kidneys  29 of 109 (27%) cases Farrington K et al. Q JMed 1989; 70: 221–233 was described by Councilman in 1898 when he examined the kidneys of patients dying of scarlet fever and diptheria Acute interstitial nephritis (AIN) is characterized by the presence of inflammatory infiltrates and edema within the interstitium, usually associated with an acute deterioration in renal function. AIN represented 1–3% of all renal biopsies in some studies

ETIOLOGY Review of three series with a total of 128 patients Etiology   Review of three series with a total of 128 patients Etiology Distribution Drugs 71 % Infection-related 15 % Idiopathic 8 % Tubulointerstitial nephritis and uveitis (TINU) syndrome 5 % Sarcoidosis 1 % Kidney International (2010) 77, 956–961 Baker RJ et al.Nephrol Dial Transplant. 2004;19(1):8 A review of three series with a total of 128 patients reported the following distribution of causes of acute interstitial nephritis Drugs, with antibiotics responsible for one-third of these cases (특히 beta lactam) SLE, sjogren 도 가능. Drug-induced AIN not dose-dependent phenomenon recurrence or exacerbation can occur with a second exposure to the same drug Schubert C et al. Clin Nephrol. 2010;73(6):413

anti-tubular basement membrane (TBM) antibodies Kidney International, Vol. 60 (2001), pp. 804–817 Possible mechanism stimulation of chemokine release by the pathogen→ infiltration of leukocytes anti-tubular basement membrane (TBM) antibodies → linear staining on immunofluorescence microscopy Giuseppe andres et al.Kidney International. Vol. IJ (1978), pp, 480-91 Fig. 1. Mechanisms whereby a drug (or one of its metabolites) can induce acute interstitial nephritis (AIN). The drug can bind to a normal component of the tubular basement membrane (TBM) and act as a hapten. (B) drug can mimic an antigen normally present within the TBM or the interstitium and induce an immune response that will also be directed against this antigen. (C) The drug can bind to the TBM or deposit within the interstitium and act as a planted (“trapped”) antigen. (D) The drug can elicit the production of antibodies and become deposited in the interstitium as circulating immune complexes. T-cells may have an important pathogenetic role timeframe of illness presentation, 10 to 14 days after exposure to the drug interstitial infiltrate is primarily of lymphocytes most patients demonstrate activation of lymphocytes against drug haptens Spanou Z et al. J Am Soc Nephrol 17: 2919–2927, 2006

A 대문자: m/c involved (B granulomatous AIN 유발 약제) there are two criteria that must be met to have any confidence of an association for drugs not known to cause AIN :the patient must not be taking other drugs that might cause the disease ; and a renal biopsy must be performed to confirm that AIN is the cause of the renal failure. common with methicillin, occurring in up to 17 percent of patients who have been treated for more than 10 days. Galpin JE et al.Am J Med. 1978;65(5):756. Methicillin is no longer available in the United States. only rare cases have been described with other H-2 blockers such as ranitidineㄻ famotidine Kidney International, Vol. 60 (2001), pp. 804–817

Drugs Too large to list , however, only a few have been reported with any frequency Two criteria . Drugs cause AIN: - must not be taking other drugs renal biopsy must be performed to confirm that AIN AIN was particularly common with methicillin, occurring in up to 17 %of patients who have been treated for more than 10 days. Currently, the most common drug causes of AIN include NSAIDs, including selective COX-2 inhibitors Penicillins and cephalosporins Rifampin Sulfonamides, (TMP-SMP), furosemide, bumetanide, thiazide-type diuretics Ciprofloxacin, perhaps to a lesser degree, other quinolones Cimetidine(only rare cases have been described with other H-2 blockers such as ranitidine) Allopurinol Proton pump inhibitors(omeprazole, lansoprazole) Indinavir 5-aminosalicylates (eg, mesalamine) Drugs — The number of drugs associated with AIN is too large to list in this topic review; however, only a few have been reported with any frequency. There are many case reports and letters to the editor describing an association between a particular drug and AIN. Since rechallenge to prove a cause-and-effect relationship is not an ethical approach, there are two criteria that must be met to have any confidence of an association for drugs not known to cause AIN: the patient must not be taking other drugs that might cause the disease; and a renal biopsy must be performed to confirm that AIN is the cause of the renal failure. Many case reports lack one or both of these features. AIN was particularly common with methicillin, occurring in up to 17 percent of patients who have been treated for more than 10 days [4,10,11]. Methicillin is no longer available in the United States. Currently, the most common drug causes of AIN include [1-3,11-19]: NSAIDs, including selective COX-2 inhibitors (see "NSAIDs: Acute kidney injury (acute renal failure) and nephrotic syndrome"). Penicillins and cephalosporins Rifampin Sulfonamides, including trimethoprim-sulfamethoxazole and, much less often, furosemide, bumetanide, thiazide-type diuretics Ciprofloxacin and, perhaps to a lesser degree, other quinolones Cimetidine (only rare cases have been described with other H-2 blockers such as ranitidine) [20,21] Allopurinol Proton pump inhibitors, omeprazole and lansoprazole Indinavir 5-aminosalicylates (eg, mesalamine) (see "Sulfasalazine and 5-aminosalicylates in the treatment of ulcerative colitis")

CLINICAL PRESENTATION onset : from 3-5 days with a second exposure to the offending agent to as long as several weeks to many months with a first exposure latent period : rifampin -one day, NSAID -18 months N Engl J Med. 1984;310(9):563. symptoms, and signs and features of acute renal dysfunction : nausea, vomiting, malaise symptoms and/or signs of an allergic-type reaction : review of three series with a total of 128 patients symptoms or signs distribution Rash 15% Fever 27% Eosinophilia 23% Triad of rash, fever, and eosinophilia 10% However, the latent period may be as short as one day with rifampin or as long as 18 months with a NSAID. N Engl J Med. 1984;310(9):563. review of three series that totaled 128 patients with AIN (of whom 70 percent had drug-induced disease) ,these findings of a typical allergic response were relatively less common at presentation. A similar incidence of findings was reported in a second retrospective study of 60 cases [31]. In this single center study, rash, fever, eosinophilia, and the triad were observed in 21, 30, 36, and less than 10 percent of cases, respectively. Thus, the classic triad is currently less commonly observed. This is probably due to the absence of cases of methicillin-induced AIN, and (perhaps) the increased inclusion of cases not directly resulting from an allergic response [9].   Baker RJ et al.Nephrol Dial Transplant. 2004;19(1):8

CLINICAL PRESENTATION   Charles M et al.Am Fam Physician2003;67:252734,2539 granular and epithelial cell casts and free epithelial cells in acute tubular necrosis ; red cell casts as well as red and white cells in acute glomerulonephritis ; and few if any abnormalities in prerenal disease cf. RBC cast 는 GN 보다 rare FeNa 는 대개 1이상 (tubule damage 때문에) but nonoliguric ARF 나 심하지 않은 ARF 에선 1미만일수도. 21. Ranitidine-associated interstitial nephritis and Fanconi syndrome. (그림) A. white blood cell cast, three-quarters of which is filled with leukocytes B. White cell cast in which blue stained white cells (arrow) are contained within a granular cast. C. Eosinophiluria by Hansel's Stain (Panel A) and Wright's Stain (Panel B) (x1000) A B C N Engl J Med. 1986 Dec 11;315(24):1516-9

CLINICAL PRESENTATION   Total of 121 patients mean protein excretions -0.9±1.1 g/day (range 0-6 g/day) median protein excretions - 0.70 g/day (interquartile range 0.39-1.0 g/day) Concurrent nephrotic syndrome d/t MCD and MN with NSAIDs, ampicillin, rifampin, ranitidine, interferon However, occasional patients have a bland sediment with few cells or casts . Arch Intern Med. 1993;153(10):1258 Thus, a relatively normal urinalysis should not exclude the diagnosis * Eosinophiluria is considered to be present when eosinophils account for more than 1 % of urinary white cells by Hansel's stain In general, however, urinary eosinophils lack the specificity and sensitivity to either exclude or diagnose acute interstitial nephritis 4. Kidney Int. 2001;60(2):804. RPGN, renal atheroemboli 에서도 Eosinophiluria 가능! degree of variability of protein excretion is demonstrated in two retrospective series - a total of 121 patients and demonstrated mean and median protein excretions of 0.9±1.1 g/day (range 0-6 g/day) - 0.70 g/day (interquartile range 0.39-1.0 g/day) [31,34 Concurrent nephrotic syndrome due to minimal change disease or membranous nephropathy can rarely be seen with NSAIDs, and in selected cases induced by ampicillin, rifampin, interferon, or ranitidine estimated sensitivity of eosinophiluria was 67% and specificity was 83% Je´roˆme Rossert et al. Kidney International, Vol. 60 (2001), pp. 804–817

DIAGNOSIS Suspected from the history and laboratory findings Confirmed by renal biopsy - interstitial edema - marked interstitial infiltrate : T lymphocytes ,monocytes, eosinophils, plasma cells, neutrophils - tubulitis : inflammatory cells invade the tubular basement membrane - granuloma formation A B (LM Low power view) diffuse interstitial inflammatory infiltrate. One normal glomerulus (High power LM ) diffuse interstitial infiltrate of inflammatory cells (Rt) uninvolved glomerulus (Lt) Gallium scan  - role of gallium scanning in drug-induced AIN is incompletely defined. - Affected patients typically show diffuse, intense, bilateral uptake, consistent with the interstitial inflammatory infiltrate 42. clin Nephrol 1985 Aug;24(2):84-7. - gallium scan is almost always negative in acute tubular necrosis, which is the condition that most often must be differentiated from drug-induced AIN.  Thus, a positive gallium scan is suggestive of AIN in the presence of the characteristic findings. However, a negative scan does not preclude the diagnosis, since false negative results can be seen [43].

Histology C D E c.(LM,H&E stain)diffuse interstitial infiltrate with red-staining eosinophils. uninvolved glomerulus is on Lt c.(High power,LM)diffuse interstitial infiltrate of mononuclear cells, many of which are actively invading the tubules leading to disruption of the tubular basement membranes (arrows). A white cell cast is present in the tubule in the upper right corner E.(LM) granulomatous change in acute interstitial nephritis. interstitial infiltrate is seen on the left, while the granuloma is on the right. The granuloma consists of both giant cells (arrows) and epithelioid cells with abundant cytoplasm which has an amorphous red appearance. Although these findings are characteristic of sarcoid involvement in the kidney, they can be seen with any cause (drug or infection) of acute interstitial nephritis. Immunohistochemical staining increased cellular infiltrates, which consistedmostly of CD4 (A) and CD8 (C) T cells, were detected in the interstitium together with neutrophils (E)

PROGNOSIS Review of three series with a total of 128 patients Prognostic indicators (controversial) long-term outcome is worse if renal failure lasts for >3 weeks Laberke HG et al. Clin Nephrol 1980; 14: 263–273 worse prognosis with increasing age Kida H et al.Clin Nephrol 1984; 22: 55–60 degree of tubular atrophy cellular infiltration (patchy VS diffuse) degree of interstitial fibrosis final serum creatinine concentration did not correlate with the maximum value during AIN 64.1% full recovery (creatinine <132 mmol/l) 23.4% partial recovery (creatinine>132 mmol/l) 12.5% remained on renal replacement therapy Richard et al. Nephrol Dial Transplant (2004) 19 proportion recovering kidney function appears to be lower in AIN due to drugs other than methicillin. prognosis of AIN due to other inciting factors (eg, sarcoidosis, infection) is not well described. Prognostic factor 를 정립하려는 많은 연구가 있지만…. renal failure lasts for >3 weeks not useful prospectively worse prognosis with increasing age no correlation with peak creatinine concentration information from the renal biopsy  controversial These conflicting observations may be due to the patchy nature of the disease and the random sampling on renal biopsy. The infiltrate is generally most prominent at the corticomedullary boundary, and the medulla is relatively spared Laberke HG et al.Clin Nephrol 1980;14: 263–273 Kidney International, Vol. 60 (2001), pp. 804–817

The outcome of acute interstitial nephritis: risk factors for the transition from acute to chronic interstitial nephritis Biomarkers for acute kidney injury such as kidney injury molecule-1 (KIM-1) and urinary neutrophil gelatinase-associated lipocalin (NGAL) may provide additional prognostic information but are not used clinically for this purpose at this time 16. Biomarkers. 2009;14(6):423 17. Kidney Int. 2009;75(3):285. Schwarz A et al.Clin Nephrol. 2000;54(3):179

MANAGEMENT Most physicians in the absence of severe disease, begin by observing the response to discontinuation of the suspected offending drug. - one study in which 17 of 27 patients with biopsy-proven AIN spontaneously improved with drug withdrawal and conservative measures Buysen JG Nephrol Dial Transplant. 1990;5(2):94 No further evaluation or therapy may be required if renal function begins to rapidly improve within several days to a week after drug withdrawal. Indications for biopsy uncertainty as to the diagnosis advanced renal failure lack of spontaneous recovery following cessation of drug therapy when early corticosteroid therapy is contemplated

Immunosuppressive therapy To treat AIN that persists despite discontinuation of the offending agent Benefits of therapy are inconclusive (no randomized controlled trials) Retrospective multicenter study effects of steroids on the recovery - lower percentage of dialysis by 18 months (4 vs 44 %) - lower serum creatinine level (2.1 vs 3.7 mg/dL) complete recovery incomplete recovery Several uncontrolled reports improvement in kidney function following glucocorticoid therapy for AIN A retrospective multicenter study examined the effects of steroids on the recovery of renal function in 52 patients with biopsy-proven drug-induced AIN compared to nine untreated patients with AIN Despite the low number of control patients, significant benefits with steroids included a lower percentage of dialysis by 18 months (4 vs 44 %) lower serum creatinine level (2.1 vs 3.7 mg/dL) Among treated patients, those who started steroids within seven days of withdrawal of the offending drug were significantly more likely to recover renal function than those who received steroids after this period (odds ratio 6.6, 95% CI 1.3-33.6). 표)Patients with DI-AIN due to NSAIDs treated with steroids 1a, complete recovery of baseline renalfunction. NSAIDs-Group 1b, incomplete recovery. González E et al.Kidney Int. 2008;73(8):940

Immunosuppressive therapy Consider corticosteroids if they do not have significant improvement in the serum creatinine within 3~7 days after discontinuation of the offending agent. prednisone  1mg/kg per day (to a maximum of 40~60 mg) for a minimum of 1~2 weeks  beginning a gradual taper after the serum creatinine has returned to or near baseline (most patients will improve in the first 1~2 weeks)  for a total therapy duration of 2~3 months More severe acute renal failure  therapy may be initiated with intravenous methylprednisolone (0.5~1 g/day for 3days) corticosteroids therapy is reasonable for potential for benefit and the relative safety of short-term therapy, if they do not have significant improvement in the serum creatinine within 3~7 days after discontinuation of the offending agent. An empiric trial of glucocorticoid therapy is a reasonable alternative in patients with a strongly suggestive history of acute drug-induced AIN when kidney biopsy is not feasible The optimal dose and duration of therapy are unclear.

Immunosuppressive therapy glucocorticoid-dependent (ie, relapse during the prednisone taper) glucocorticoid-resistant (as with NSAID-induced disease) cannot tolerate glucocorticoids Largest reported experience included 8 patients with biopsy-proven AIN Glucocorticoids for at least 6 months and could not discontinue therapy MMF was given for 13 to 34 months Cr 2.31.6 (only 2 patients had no improvement in serum creatinine) All were able to discontinue corticosteroids only 2 patients had no improvement in serum creatinine (one who was ANCA-positive and one with AIN of unknown etiology). The applicability of these results to drug-induced AIN is limited, since only two patients had AIN known to be due to drugs. MMF may be considered only in patients who are glucocorticoid-dependent, glucocorticoid-resistant, or unable to tolerate glucocorticoid therapy and have biopsy-proven AIN. Preddie DC et al.Clin J Am Soc Nephrol. 2006;1(4):718

The merits of immunosuppressive agents, specifically cyclophosphamide or cyclosporine, are even less certain. They can be used as steroid-sparing agents and should be considered for patients who fail to respond to a 2-week course of steroid therapy. 4-week course of cyclophosphamide (2 mg/kg of body weight per day) while renal function and white blood cell count are monitored should suffice to determine response. Therapy for longer than 4 to 6 weeks is not indicated. Brenner and Rector's The Kidney, 9th ed. 2011 Saunders pp1343 anecdotal use of cyclophosphamide (Drug rash with eosinophilia and systemic symptomes) Case of vancomycin induced DRESS syndrome with acute in terstitial nephritis. No improvement after withdrawal of the offending agent and empiric corticosteroid use. After tapering the steroids, a five-day course of cyclosporine (100 mg bid) was followed by resolution of the skin rash and recovery of renal function. Zuliani E et al.Clin Nephrol. 2005;64(2):155

Results : Acute TIN was identified in 24 (8. 1%) biopsies Results : Acute TIN was identified in 24 (8.1%) biopsies. Eight out of 14 cases with presumed drugrelated TIN could be attributed to the proton pump nhibitors omeprazole and lansoprazole. Conclusion. :Drugs are the most common cause of interstitial nephritis in the population studied. Those drugs most commonly associated with interstitial nephritis were the proton pump inhibitors omeprazoleand lansoprazole

25 published reports of AIN associated with H2 antagonists: 20 cases with cimetidine, 4 with ranitidine, and 1 with famotidine (table I). They developed AIN between 2 days and 11 months The diagnosis of AIN was confirmed by renal biopsy in 18 cases.

25 published reports of AIN associated with H2 antagonists: 20 cases with cimetidine, 4 with ranitidine, and 1 with famotidine (table I). They developed AIN between 2 days and 11 months after commencing H2 antagonist therapy. The diagnosis of AIN was confirmed by renal biopsy in 18 cases.