Tuesday Clinical Case conference

10/ 2007 , Zae Kim MD

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

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

Causes

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

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

Epidemiology

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

: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

: 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

: 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

: 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

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

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

?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

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

– ?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

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

Pathophysiology

– 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

Based on Experimental AIN

http://www.nature.com/ki/journal/v60/n2/fig_tab/4492487f1.html#figure-title

- 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

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

• 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

… 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

- 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

- 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

- 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

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

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

: 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

: 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

Effect of corticosteroid therapy in AIN compared with . conservative management

Values for serum creatinine (µmol/l) are given as median±interquartile range.

?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

The end