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Tuesday Clinical Case conference

This clinical case conference discusses the etiology, diagnosis, and prognosis of acute interstitial nephritis, an immune-mediated cause of acute renal failure. It provides insights into the incidence, causes, and clinical manifestations of the condition, as well as noninvasive diagnostic procedures and the histopathological findings. The conference also examines the prognostic factors and course of renal function recovery in patients with drug-induced acute interstitial nephritis.

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Tuesday Clinical Case conference

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

  2. 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 literatureregarding optimal management of the condition

  3. 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

  4. Causes

  5. The changing profile of acute tubulointerstitial nephritisBacker 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

  6. 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

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

  8. Noninvasive diagnostic procedure:eosinophiluria • 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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 > 2.2 Crt <1.2 Crt 1.2 – 2.2 Rossert, KI, 2001

  16. 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

  17. 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

  18. Pathophysiology

  19. 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

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

  21. Involvement of Drug-Specific T cells in Acute Drug-Induced Interstitial NephritisSpanou 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

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

  23. 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

  24. 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 #Even though there were multi drug exposure, each patient elicited proliferative response to only one drug Involvement of Drug-Specific T cells in Acute Drug-Induced Interstitial Nephritis Spanou et al, JASN, 17: 2919, 2006

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

  26. Total CD4 317/mmsq TCR-Vb* 27 mm/sw 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 272/mmsq • TCR-Vb* 120/mmsq • Both show extensive T cell infiltrate • Both stained for TCR-Vb* specific to flucloxacillin (normally found on 4-7% of circulating T cell only)

  27. Involvement of Drug-Specific T cells in Acute Drug-Induced Interstitial NephritisSpanou 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

  28. Treatment • Therapy aimed at modulating the immune response has been the main treatment for AIN • Several smallretrospective studies have suggested that corticosteroid therapyimproves 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

  29. 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

  30. Acute interstitial nephritis: a clinical and morphological study in 27 patientsBuysen 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

  31. Acute interstitial nephritis: clinical features and response to corticosteroid therapyClarkson et al, Nephrology Dialysis Transplantation 2004 19(11):2778-2783 • a retrospective studyof all cases (n=60) of AIN found by reviewing 2598 native renal biopsiesover a 12 year period • Of those patients in whom complete follow-up data were available(n = 42) • 60% received corticosteroid therapy while the remainderreceived supportive care only

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

  33. 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

  34. The end

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