1. Tuesday Clinical Case conference 10/2007 Zae Kim, MD

4. Acute Interstitial 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

5. 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

6. Causes

7. The changing profile of acute tubulointerstitial nephritis Backer RJ; Pusey CD, Nephrol Dial Transplant 2004 Jan;19(1):8-11 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

8. Approximated frequency with which clinical manifestations 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

9. Epidemiology The overall picture that emerges is of a syndrome that is becoming both –increasingly non-specific in clinical features –diverse in etiology

10. Noninvasive diagnostic procedure: eosinophiluria Number of patients6592183199539 Patients with AIN Eosinophiluria81056 29 (63%) No eosinophiluria113914 Patients without AIN Eosinophiluria2712151064 No eosinophiluria2969160174 432 (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

11. 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

12. 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 67 gallium scintigraphy to identify reliably non-infectious interstitial nephritis. J Nucl Med 1983 24:568–570

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. Pathophysiology

21. 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

22. Based on Experimental AIN http://www.nature.com/ki/journal/v60/n2/fig_tab/4492487f1.html#figure-title

23. Involvement of Drug-Specific T cells in Acute Drug-Induced Interstitial Nephritis Spanou et al, JASN, 17: 2919, 2006 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

24. 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 2 Tx for endocarditis, arf after 8 days Pt 3 ARF after 3 weeks

25. 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

26. 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

27. T cell receptor Vb expression in a drug-specific T cell line by flow cytometry 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

28. 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

29. Involvement of Drug-Specific T cells in Acute Drug-Induced Interstitial Nephritis Spanou et al, JASN, 17: 2919, 2006 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

30. 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

31. 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

32. Acute interstitial nephritis: a clinical and morphological study in 27 patients Buysen et al, Nephrol Dial Transplant. 1990;5(2):94-9 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 following admission prednisone therapy was instituted All with improvement of renal function –with six returning to normal

33. Acute interstitial nephritis: clinical features and response to corticosteroid therapy Clarkson et al, Nephrology Dialysis Transplantation 2004 19(11):2778-2783 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

34. Effect of corticosteroid therapy in AIN compared with conservative management. Values for serum creatinine (µmol/l) are given as median±interquartile range.

35. 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

36. The end