Tuesday Clinical Case conference

10/2007
Zae Kim, MD
 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
 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
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
 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
 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 procedure:
eosinophiluria

Number of patients 65 92 183 199 539

Patients with AIN          
29
  Eosinophiluria 8 10 5 6
(63%)
  No eosinophiluria 1 1 3 9 14
Patients without AIN        
  Eosinophiluria 27 12 15 10 64
432
  No eosinophiluria 29 69 160 174
(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 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
 Pt 1. Pt 2 Pt 3
Tx’d w abx for Tx for ARF after 3
endocarditis, endocarditis, arf weeks
developed ARF 3 after 8 days
weeks after starting
abx

Involvement of Drug-Specific T cells in Acute Drug-Induced Interstitial Nephritis Spanou et al, JASN, 17: 2919, 2006
 • 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. Pt 2 Pt 3
Positive proliferative PBMC proliferative PBMC proliferative
response of PBMC to response to penicillin G response to disulfiram
flucloxacillin
#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
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
 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 • Total CD4 317/mmsq

• TCR-Vb* 120/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)
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
 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 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
 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
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