22 kim acute interstitial nephritis
TRANSCRIPT
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Tuesday Clinical Case conference
10/ 2007 , Zae Kim MD
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Acute Interstitia l nephritis
• Term first used by Councilman in 1898– Noted the histopathologic changes in autopsy
specimens of patients with diptheria and scarlet fever
• Immune-mediated cause of acute renal failure– Characterized by presence of an inflammatory cell
infiltrate in the renal interstitium and tubules
• there is a paucity of data in the literature
regarding optimal management of the condition
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Incidence
• Significant cause of acute renal failure– series of 109 patients from a large center– biopsied for unexplained renal impairment with
normal sized kidneys– AIN accounted for 29 of 109 (27%) cases
– Farrington K, Levison DA, Greenwood RN, Cattell WR, Baker LR. Renal biopsy in patients with unexplained renal impairment and normal kidney size. Q J Med 1989; 70: 221–233
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Causes
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The changing profile of acute tubulointerstitial nephritis
; , 2004 ;19(1):8-11Backer RJ Pusey CD Nephrol Dial Transplant Jan
• A review of three series that totaled 128 pts – (71%) Drugs, with antibiotics responsible for 1/3– (15%) Infection-related– (8%) Idiopathic– (5%) Tubulointerstitial nephritis and uveitis (TINU)
syndrome– (1%) Sarcoidosis
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Approxim a te d fre que ncy with which clinica l ma nife s ta tions …occur during
(A) methicillin-induced AIN(B) AIN induced by drugs other than methicillin(C) AIN induced by NSAIDs and associated with a nephrotic syndrome
http://www.nature.com/ki/journal/v60/n2/full/4492487a.html#fig2
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Epidemiology
• The overall picture that emerges is of a syndrome that is becoming both – increasingly non-specific in clinical features – diverse in etiology
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:Noninvasive diagnostic procedureeosinophiluria
Number of patients 65 92 183 199 539
Patients with AIN
Eosinophiluria 8 10 5 629 (63%)
No eosinophiluria 1 1 3 9 14
Patients without AIN
Eosinophiluria 27 12 15 10 64
No eosinophiluria 29 69 160 174432 (87%)
• Corwin, HL, Korbet, SM, Schwartz, MM: Clinical correlates of eosinophiluria. Arch Intern Med 1985 145:1097–1099• Nolan, CR, Anger, MS, Kelleher, SP: Eosinophiluria: A new detection and definition of the clinical spectrum. N Engl J Med 1986 315:1516–1519• Corwin, HL, Bray, RA, Haber, MH: The detection and interpretation of urinary eosinophils. Arch Pathol Lab Med 1989 113:1256–1258• Ruffing, KA, Hoppes, P, Blend, D, et al: Eosinophils in urine revisited. Clin Nephrol 1994 41:163–166
http://www.nature.com/ki/journal/v60/n2/fig_tab/4492487t2.html#figure-title
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: Noninvasive diagnostic procedure – ?Gallium scan highly sensitive
• Gallium67 scintigraphy in the diagnosis of acute renal disease. Linton et al, Clin Nephrol.
1985 Aug;24(2):84-7.– N = 44 patients with various biopsy proven renal
disease• AIN = 11 patients• Two blinded observers
– Result• All 11 AIN (100%)• 5/33 (15%) of other renal disease had (+) uptake
– Glomerulonephritis, pyelonephritis
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: Noninvasive diagnostic procedure – ?Gallium scan not highly sensitive
• N = 16 with AIN– (+) gallium scan in 11/16 (68%)– Koselj, M, Kveder, R, Bren, AF, Rott, T: Acute renal failure in patients
with drug-induced acute interstitial nephritis. Ren Fail 1993 15:69–72
• N = 12 with AIN– (+) gallium scan in 7/12 (58%)– Graham, GD, Lundy, MM, Moreno, JJ: Failure of 67gallium scintigraphy
to identify reliably non-infectious interstitial nephritis. J Nucl Med 1983 24:568–570
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: Lab biopsy
• Inflammation of renal interstitium– Microscopically
• Multifocal cellular infiltration and edema• Mononulcear cells (lymphocytes and macrophages) usually
are the predominant types• Drug reaction
– Mononuclear cells, typically T cells (CD4>CD8)
• Glomerular and vascular sparing
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Course
• Based on the course of methicillin-induced AIN– drug-induced AIN has long been considered a
relatively benign nephropathy– complete recovery of renal function was supposed to
be the rule if the inciting agent was removed
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Analysis of published cases of AIN by drugs other than methicillin
course of renal function recovery
• At the end of follow up– Only 68% had
sCr <1.7– Only 40% had
sCr <1.2
68% w crt < 1.7
49% w crt < 1.2
Rossert, KI, 2001
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?Prognostic factor
• could we identify patients with drug-induced AIN who are at high risk of incomplete recovery?– Severity of renal failure?– Histology
• Diffuse vs patchy infiltrate• Degree of fibrosis
– Duration of renal failure
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Severity of renal function as prognostic? marker
• Patients were arbitrarily divided into three groups depending on serum creatinine levels at the end of follow-up
• Maximum serum creatinine levels did not differ among these three groups
Crt <1.2 Crt 1.2 – 2.2 Crt > 2.2
Rossert, KI, 2001
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– ?Prognostic factor histology
• Diffuse vs patch interstitial infiltrates– n = 30, less favorable renal prognosis with diffuse vs
patch• sCr ~2 in 10/18 with diffuse (55%)• sCr ~1.1 in 9/12 w patch (75%)
» Laberke, HG & Bohle, A: Acute interstitial nephritis: Correlation between clinical and morphological findings. Clin Nephrol 1980 14:263–273
– Two other studies (n = 27 and 14) no correlation» Kida, H, Abe, T, Tomosugi, N, et al: Prediction of the long-term outcome in
acute interstitial nephritis. Clin Nephrol 1984 22:55–60» Buysen, JGM, Houtlhoff, HJ, Krediet, RT, Arisz, L: Acute interstitial
nephritis: A clinical and morphological study in 27 patients. Nephrol Dial Transplant 1990 5:94–99
– Conflicting result
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Prognostic factor
• Duration of acute renal failure– N = 30
• Mean sCr ~1.4 with ARF < 2 wks• Mean sCr ~3.4 with ARF > 3 wks
» Laberke, Acute interstitial nephritis, Clin Nephrol 14:263, 1980
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Pathophysiology
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– Pathophysiology drug induced AIN
• Drug-induced AIN is secondary to immune reaction– AIN occurs only in a small percentage of individuals taking the
drug– AIN is not dose-dependent– Association with extrarenal manifestations of hypersensitivity– Recurrencence after re-exposure to the drug
• Experimental models– Suggest that drugs responsible for AIN induce an immune
reaction directed against endogenous renal antigens
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Based on Experimental AIN
http://www.nature.com/ki/journal/v60/n2/fig_tab/4492487f1.html#figure-title
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- Involvement of Drug Specific Tcells in Acute- Drug Induced Interstitial Nephritis
, , 17: 2919, 2006Spanou et al JASN
• Role of drug-specific responses in patients with a histologic diagnosis of DIN (Drug-Induced Nephritis)
• Identified drug-specific T cells• Characterized them phenotypically in vitro
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Involvement of Drug-Specific T cells in Acute Drug-Induced Interstitial Nephritis Spanou et al, JASN, 17: 2919, 2006
Pt 1.Tx’d w abx for endocarditis, developed ARF 3 weeks after starting abx
Pt 2Tx for endocarditis, arf after 8 days
Pt 3ARF after 3 weeks
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• Lymphocyte Transformation Test (LTT) used to analyze drug-specific proliferation of patients PBMC– Relies on observation that T cells divide and expand
after encountering the antigen– Measures H-thymidine uptake of dividing cells
Involvement of Drug-Specific T cells in Acute Drug-Induced Interstitial Nephritis Spanou et al, JASN, 17: 2919, 2006
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… Lymphocyte Transformation Test- Drug specific proliferation of patients PBMC
Pt 1.
Positive proliferative response of PBMC to flucloxacillin
Pt 2
PBMC proliferative response to penicillin G
Pt 3
PBMC proliferative response to disulfiram
Involvement of Drug-Specific T cells in Acute Drug-Induced Interstitial Nephritis Spanou et al, JASN, 17: 2919, 2006
#Even though there were multi drug exposure, each patient elicited proliferative response to only one drug
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- Tcell receptor Vb expression in a drug specific Tcell line by flowcytometry
• PBMC of pt 1 was incubated with flucloxacillin and IL-2
• CD3+ T cells bearing Vb9 and Vb21.3 were enriched
• Suggesting an oligoclonal T cell expansion
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- TCR Vb staining in kidney biopsy specimens- - to determine whether the drug specific T cells from PBMC might be present in the kidney
• Total CD4 317/mmsq• TCR-Vb* 27 mm/sw
• Both show extensive T cell infiltrate• Both stained for TCR-Vb* specific to flucloxacillin (normally found on 4-7% of circulating T cell only)
• Total CD4 272/mmsq• TCR-Vb* 120/mmsq
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- Involvement of Drug Specific Tcells in Acute- Drug Induced Interstitial Nephritis
, , 17: 2919, 2006Spanou et al JASN
• Implications…– In vitro proliferation assays might be helpful to
identify the drug that is responsible for the hypersensitivity reaction
• Particularly in patients with more than one medication exposure
– It’s likley that the T cell infiltration into the kidney is due to drug-specific T cells, which then might coordinate the local inflammatory reaction
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Treatment
• Therapy aimed at modulating the immune response has been the main treatment for AIN
• Several small retrospective studies have suggested that corticosteroid therapy improves clinical outcome; however, no prospective studies exist
• Pusey CD, Saltissi D, Bloodworth L, Rainford DJ, Christie JL. Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy. Q J Med 1983; 52: 194–211
• Buysen JG, Houthoff HJ, Krediet RT, Arisz L. Acute interstitial nephritis: a clinical and morphological study in 27 patients. Nephrol Dial Transplant 1990; 5: 94–99
• Enriquez R, Gonzalez C, Cabezuelo JB et al. Relapsing steroid-responsive idiopathic acute interstitial nephritis. Nephron 1993; 63: 462–465
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Retrospective study
Drug associated acute interstitial nephritis: clinical and pathological features and the response to high dose steroid therapy.Pusey et al, Q J Med 1983
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: Acute inte rs titia l ne phritis a c linica l and 2 7 morphologica l s tudy in patie nts
, Buys e n e t a l . 1990;5(2):94-9Nephrol Dial Transplant
• N = 27 biopsy-proven AIN– 17 patients
• renal function improved after withdrawal of the drug
– 10 patients• Further decline in renal function in the two weeks
fol lowing admission• prednisone therapy was instituted • All with improvement of renal function
– with six returning to normal
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: Acute inte rs titia l ne phritis c linica l fe a ture s and re s pons e to corticos te roid
the rapy , Clarks on e t a l 2004 19(11):2778-2783Nephrology Dialysis Transplantation
• a retrospective study of all cases (n=60) of AIN found by reviewing 2598 native renal biopsies
over a 12 year period– Of those patients in whom complete follow-up data
were available (n = 42)• 60% received corticosteroid therapy while the remainder
received supportive care only
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Effect of corticosteroid therapy in AIN compared with . conservative management
Values for serum creatinine (µmol/l) are given as median±interquartile range.
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?Why no benefit
• Patients treated with steroids had more severe disease
• Significant proportion of the patients had NSAID-associated AIN, which is less likely to respond to steroid tx
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The end