Tuesday Clinical Case conference

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Tuesday Clinical Case conference
10/2007 Zae Kim, MD
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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

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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 221233

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Causes
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The changing profile of acute tubulointerstitial
nephritisBacker RJ Pusey CD, Nephrol Dial
Transplant 2004 Jan19(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

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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/44924
87a.htmlfig2
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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

• Corwin, HL, Korbet, SM, Schwartz, MM Clinical
  correlates of eosinophiluria. Arch Intern Med
  1985 14510971099
• Nolan, CR, Anger, MS, Kelleher, SP
  Eosinophiluria A new detection and definition of
  the clinical spectrum. N Engl J Med 1986
  31515161519
• Corwin, HL, Bray, RA, Haber, MH The detection
  and interpretation of urinary eosinophils. Arch
  Pathol Lab Med 1989 11312561258
• Ruffing, KA, Hoppes, P, Blend, D, et al
  Eosinophils in urine revisited. Clin Nephrol 1994
  41163166

http//www.nature.com/ki/journal/v60/n2/fig_tab/44
92487t2.htmlfigure-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
  Aug24(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 156972
• 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 24568570

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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 (CD4gtCD8)
• 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 lt1.7
• Only 40 had sCr lt1.2

68 w crt lt 1.7
49 w crt lt 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 lt1.2
Crt gt 2.2
Crt 1.2 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
  14263273
• 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 225560
• Buysen, JGM, Houtlhoff, HJ, Krediet, RT, Arisz,
  L Acute interstitial nephritis A clinical and
  morphological study in 27 patients. Nephrol Dial
  Transplant 1990 59499
• Conflicting result

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Prognostic factor

• Duration of acute renal failure
• N 30
• Mean sCr 1.4 with ARF lt 2 wks
• Mean sCr 3.4 with ARF gt 3 wks
• Laberke, Acute interstitial nephritis, Clin
  Nephrol 14263, 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/44
92487f1.htmlfigure-title
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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

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Pt 1. Txd 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
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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
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
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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

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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

• 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)

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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
• Its 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 194211
• Buysen JG, Houthoff HJ, Krediet RT, Arisz L.
  Acute interstitial nephritis a clinical and
  morphological study in 27 patients. Nephrol Dial
  Transplant 1990 5 9499
• Enriquez R, Gonzalez C, Cabezuelo JB et al.
  Relapsing steroid-responsive idiopathic acute
  interstitial nephritis. Nephron 1993 63 462465

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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 interstitial nephritis a clinical and
morphological study in 27 patientsBuysen et al,
Nephrol Dial Transplant. 19905(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

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Acute interstitial nephritis clinical features
and response to corticosteroid therapyClarkson
et al, Nephrology Dialysis Transplantation 2004
19(11)2778-2783

• a retrospective study of all cases (n60) 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
medianinterquartile 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