Tubulointerstitial kidney diseases: Pathophysiology ... NORTIER compressed.pdf ·...

Tubulointerstitial kidney diseases:

Pathophysiology, diagnosis and

clinical management

Joëlle Nortier, MD, PhD

Nephrology Dept & Lab. Experimental Nephrology

Faculty of Medicine, Université Libre de Bruxelles

Belgian Core Curriculum Course Nephrology

June 16, 2018

CONTENT

1) Definitions / characteristics

2) Acute interstitial nephritis: pathophysiology, diagnosis, clinical cases & management

3) Chronic interstitial nephritis: pathophysiology, diagnosis, clinical cases & management

15 juin 2018 4

1) DEFINITION / TERMINOLOGY

Group of diseases primarily manifested by

inflammation and/or injury of renal tubules and

interstitium

Synonyms: (tubulo)interstitial nephritis

Abbreviations

Acute interstitial nephritis (AIN)

Chronic interstitial nephritis (CIN)

Acute tubular necrosis (ATN)

Acute tubular injury (ATI)

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AIN >< CIN: CHARACTERISTICS

Acute IN

Acute, often reversible disease

Inflammatory infiltrates within

the interstitium

Uncommon cause of AKI (<

5%)

Up to 25% of renal biopsies for

drug-induced AKI

Bilateral flank pain

Increased size and

echogenicity of the kidneys

Mild proteinuria (< 1g/day)

Chronic IN

Frequent lesions reflecting the

progressive degradation of

renal function

Primary forms of CIN reaching

ESRD are quite rare

15% to 20% of CKD

Insidious development of renal

insufficiency

Anemia, hypertension…

Signs of proximal tubular

dysfunction…

Mild proteinuria (< 1g/day)

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AIN >< CIN: MAIN ETIOLOGIES & HISTOLOGICAL FINDINGS

Acute IN

1. Drugs

2. Infections

3. Autoimmune diseases

Nonspecific lesions

variable size of enlarged

interstitial compartment (edema +

inflammatory infiltrate)

! No vascular or glomerular

lesions

! No immune deposit in most

cases…

Chronic IN

1. Toxins

2. Infections

3. Systemic diseases

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Typical histological findings in case of

AIN : interstitial inflammatory infiltrate

with edema and tubular lesions (HE

staining)

7

Normal renal cortex (PAS staining)

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AIN >< CIN: MAIN ETIOLOGIES & HISTOLOGICAL FINDINGS

Acute IN

1. Drugs

2. Infections

3. Autoimmune diseases

Nonspecific lesions

variable size of enlarged

interstitial compartment (edema +

inflammatory infiltrate)

! No vascular or glomerular

lesions

! No immune deposit in most

cases…

Chronic IN

1. Toxins

2. Infections

3. Systemic diseases

Interstitial fibrosis

Tubular cell atrophy

Mononuclear cell infiltration

(variable intensity)

Noncaseating granulomatous

patterns in specific situations

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Typical lesions of hypertensive

nephroangiosclerosis

Remodelling of arterial walls (thickening

of the media and intimal fibrosis),

tubular atrophy and interstitial fibrosis

9

Normal renal cortex (PAS staining)

CONTENT




Pathogenesis of AIN (experimental models)

1. Drug-induced AIN Antimicrobial agents Antiviral agents Nonsteroidal anti-inflammatory drugs

(NSAIDs) including salicylates Antalgics Antiulcer agents (cimetidine and proton

pump inhibitors) Anticonvulsants Diuretics

hypersensitivity reaction, not dose dependent

Clinical presentation (within days after drug ingestion): Low-grade fever Maculopapular rash Mild arthralgias Eosinophilia

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SPECIFIC DRUG ASSOCIATIONS

Rifampicin: usually after readministration of the

drug; fever and gastrointestinal syptoms and

myalgias; hemolysis and thrombocytopenia,

hepatitis

Allopurinol: more frequent in CKD patients; rash +

liver dysfunction !

NSAIDs (including COX-2 selective inhibitors):

nephrotic syndrome (75% cases; 50 % of cases

with fenoprofen): after months of regular intake

(even more than 1 year); edema ++ but no other

extrarenal symptoms

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On light microscopy, search

for the characteristic features

- Interstitial infiltration with

mononuclear cells

(eosinophils)

- Usually associated with

interstitial edema and

tubular lesions

- Some drugs can induce

the formation of interstitial

granulomas, reflecting a

delayed-type

hypersensitivity reaction

15

PATHOLOGY OF DRUG-INDUCED ACUTE INTERSTITIAL NEPHRITIS

(Courtesy of Pr. I. Brochériou)

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15 juin 2018 17 17

INFLAMMATORY INFILTRATES IN ACUTE INTERSTITIAL NEPHRITIS

- Often patchy , predominating in the deep cortex and in

the outer medulla

- Can be diffuse in most severe diseases

- Composed mostly of T cells and monocyte-macrophages

+ eosinophils, plasma cells may be present… a few

neutrophilic granulocytes

- CD4+ and CD8+ T cells in variable proportions

- Signs of tubulitis: T cells infiltrate across the tubular

basement membrane and between tubular cells (mainly

in distal tubules)

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15 juin 2018 19

Interstitial granulomas

- Sparse and non-necrotic

- With few giant cells

- Associated with

nongranulomatous

interstitial infiltrates

!!!! Granulomas are also

found in AIN related to

infections, sarcoidosis,

Sjögren’s syndrome and

Wegener’s granulomatosis



15 juin 2018 20

Immunofluorescence may be

positive !

- Staining of the tubular basement

membrane for IgG or

complement

- Granular or linear staining

pattern…. Indicating the

presence of antibodies directed

against membrane antigens or

against drug metabolites bound

to the membrane

- Mostly seen in patients taking

methicillin, NSAIDS, phenytoin,

allopurinol

20


Linear deposits of IgG in a case of methicillin-

induced AIN (Courtesy of Dr. B. Mougenot)

!!! ACUTE INTERSTITIAL NEPHRITIS >< ACUTE TUBULAR NECROSIS

Interstitial inflammatory

infiltrate

Tubulitis

Granulomas

Tubular granular casts

Loss of the brush border

Necrosis of the tubular cells

Polymorphonuclear

neutrophils in the vasa recta

Hyaline, granular casts

- The most frequent form of

AKI (85%)

- Ischemic or toxic origin

21

CISPLATIN NEPHROTOXICITY

Acute and focal tubular necrosis

Signs of tubular regeneration

Diagnosis of drug-induced AIN

RENAL BIOPSY !

and also…

- Eosinophiliuria but low sensitivity and low positive predictive value

- Gallium-67 renal scanning but not specific (positive in case of cancer, pyelonephritis…)

In Comprehensive Clinical Nephrology, 3rd ed.

15 juin 2018 24

IDENTIFICATION OF THE CAUSATIVE AGENT

Not so easy in patients with polymedication !

2 tests but of limited diagnostic value:

- antidrug circulating antibodies (rifampicin)

- lymphocytic stimulation test: proliferative index is

associated with a sensitization of T lymphocytes against

the suspected drug

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IDENTIFICATION OF THE CAUSATIVE AGENT / NATURAL HISTORY

Not so easy in patients with polymedication !

2 tests but of limited diagnostic value:

- antidrug circulating antibodies (rifampicin)

- lymphocytic stimulation test

NATURAL HISTORY

Disappearance of extrarenal Ʃ within 2 weeks

Recovery of renal function is often delayed (average

recovery time 1.5 months)

Prognostic factors

Duration of AKI

Severity of interstitial fibrosis

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2. AIN SECONDARY TO INFECTIONS: MAIN CAUSES

Bacteria

Staphylococcus spp.

Streptococcus spp.

Tuberculosis spp.

Legionella spp.

Leptospirosis spp.

Chlamydia spp.

Mycoplasma spp.

26

Viruses Cytomegalovirus Epstein-Barr virus Hantaan Hepatitis A and B Herpes simplex virus HIV Rickettsia

Parasites Toxoplasma Leischmania donovani

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= infection of the renal parenchyma

In 95% of cases: secondary to

ascending infection of the urinary

tract

Gram neg (E Coli), strepto, staph…

27

ACUTE PYELONEPHRITIS

Predominance of polymorphonuclear

neutrophils (PMN) in the interstitial

inflammatory infiltrate


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« Hemorrhagic fever with renal

syndrome », « epidemic

hemorrhagic fever »

- Extrarenal Ʃ: fever, headache,

lightheadedness, abdominal pain,

nausea, vomiting

- Thrombocytopenia

- Acute renal failure; proteinuria in

the nephrotic range, hematuria

- IF: granular immune deposits

balong the TBM or within glomeruli

- Δ: serologic tests

- Complete recovery is the rule but

may be complicated by

hemorrhagic episodes or shock

28

HANTAVIRUS INFECTIONS: A WORLDWIDE PROBLEM

Vascular congestion and foci of medullary hemorrhage are suggestive of the diagnosis

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3. AIN ASSOCIATED WITH SYSTEMIC DISEASES

Sarcoidosis

Gougerot Sjögren (rare)

Systemic lupus erythematosus (rare with minimal

glomerular abnormalities; granular pattern of immune deposits along

the TBM)

IgG4 related diseases

ΔΔ AIN associated with malignancies

Idiopathic AIN (TINU syndrome):

anterior uveitis, in pubertal girls/boys…ocular pain and

visual impairment, pseudoviral Ʃ; good response to

steroid therapy

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1. Hypercalcemia and hypercalciuria

renal dysfunction

2. AKI with mild proteinuria

- Extrarenal Ʃ in 90% cases: lymph

nodes, lung, eye, liver

- Hilar lymphadenopathy or pulmonary

interstitial fibrosis in 1 /2 cases at the

time of Δ

- High-dose corticosteroids are

mandatory (1 mg/kg prednisone

daily), slow tapering… min 9-12

months

30

SARCOIDOSIS AND RENAL INVOLVEMENT

Granulomatous AIN in a patient with

sarcoidosis (Courtesy of Dr. B. Mougenot)

IGG4 RELATED DISEASES

31

IgG4-related tubulointerstitial nephritis and/or glomerulonephritis

32

AI pancreatitis

AI interstitial nephritis

Corticosteroids Corticosteroids + azathioprine

A CASE OF IGG4 RELATED ACUTE INTERSTITIAL NEPHRITIS…

33

IgG4 immunostaining (medulla)

Severe interstitial inflammation

Clin Kidney J (2012) 5: 225

Management of AIN

• Dependent upon the underlying disease process

• Drug-induced AIN: identify and stop offending drug early steroid treatment may improve the recovery of renal function !! If worsening renal function or requiring RRT: prednisolone 1 mg/kg/day orally, taper over a period of 1 month according to the response (bone and GI protection + monitor glucose)

!! NSAID-induced AIN is less responsive to corticosteroid therapy MMF has been used in patients with steroid-resistant AIN

Blue bars: patients treated with corticosteroids Yellow bars: patients free of corticosteroids

CONTENT




MAJOR ETIOLOGIES OF CHRONIC INTERSTITIAL NEPHRITIS

Kidneys are

macroscopically normal

Drugs and toxins

Metabolic

Heavy metals (Pb, Cd, As,

Hg)

Radiation

Atherosclerosis

Hematologic disturbances

(multiple myeloma)

Progressive glomerular

disease of all etiologies

Kidneys are

macroscopically abnormal

Analgesic nephropathy

Chronic obstruction

Hereditary

Infection

36

CHRONIC PYELONEPHRITIS

Almost exclusively in case of

obstruction of urinary tract or

reflux nephropathy

37


TWO PARTICULAR CASES OF CHRONIC PYELONEPHRITIS…

Women 50-60 yrs

Unilateral flank pain,

fever, anorexia, weight

loss, nausea

Biol: inflammatory

syndrome

Pyuria; Gram neg (E.

Coli, Proteus sp.,

Pseudomonas

aeruginosa)

38

39

Histiocytes and large

macrophages

Xanthogranulomatous

pyelonephritis

A 2ND CASE…

Man 60 yrs, kidney recipient (2nd)

SP/acute pyelonephritis (E. Coli)

and prostatitis (Enterococcus

faecalis)

Fever and diarrhea

Renal graft degradation; urinary

infection (E. Coli)

Fluoroquinolone therapy but no

improvement of renal function

kidney biopsy

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41

Diagnosis ??

RENAL MALAKOPLAKIA

First described in 1902 by Michaelis and Gutmann

Genito-urinary tract (bladder +++)

Bilateral renal localization (35-50 %)

3 F / 1 H (peak 50-60 yrs)

Microscopy: interstitial infiltration by macrophages

containing concentric cytoplasm inclusions (5-10 µ) =

Michelis Gutmann bodies; bacterial residues + for Ca and

Fe

Pathogenesis: BGN infections (E. Coli) + primary defect of

macrophages (altered degranulation process)

42

CHRONIC URATE NEPHROPATHY

Hyperuricemia

Hypertension

Gout for many years

44 The crystalline masses are refractile under

polarized light

Aristolochic acid I + II (R=OCH3 / H)

«Stephania Tetrandra»

Han Fang-Ji

Vanherweghem et al. Lancet (1993); Vanhaelen et al. Lancet (1994)

Guang Fang-Ji

Aristolochia fangchi

Aristolochic acid nephropathy

Depierreux et al. Am J Kidney Dis 1994

Cosyns et al. Kidney Int 1994

Autoradiogram of specific AA-related

DNA adducts in renal tissue

Schmeiser HH, Arlt VM. Cancer Res (1996)

Arlt VM. Mutagenesis (2002)

AA biotransformation

(cytochrome P450)

AA-associated urothelial malignancies

Cosyns et al. Am J Kidney Dis (1999)

Nortier et al. N Engl J Med (2000)

Right ureteral tumor

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Select cystoscopy screening suggests a stage migration toward

detection of non-muscle-invasive bladder cancer (BC)

Kidney recipients, n 48

Patients lost to follow-up 2

Median follow-up, months 90.5 ± 36

Bladder cancer, no. 25 (52 %)

Noninvasive BC at first diagnosis, no. 22 (46 %)

Muscle-invasive BC at first diagnosis in 0 (0 %)

patients who accepted screening, no.

Patient-refused follow-up / Deaths, no. 3 (6%)

Zlotta et al. Eur Urol 2011:59:1026-31 49

What about outside Belgium ?

Debelle et al. Kidney Int. (2008) 74:158

?

?

p53 mutations in AAN:

a case report of an English AAN patient

ureter: carcinoma in situ

Laser capture microdissection of

neoplastic cell + p53 mutation analysis

mutation type tissue

urothelial tumour

codon/mutation

codon 139

(AAGTAG; LysStop)

p53exon

exon 5 A T transversion

Lord et al. (2004) Am. J. Kidney Dis. 43

Courtesy of Dr

B. Jelakovic

Aristolochia clematitis

Proposed diagnostic criteria of AAN

(European consensus panel)

Major criteria (2 out of 3 should be needed)

- Confirmed ingestion of AA by phytochemical analyses

- Histopathological demonstration of interstitial fibrosis

- Detection of specific AA-DNA adducts in renal tissue

Minor criteria (2 in association with 1 major)

- History of exposure to AA

- Presence of urothelial carcinoma

Gökmen MR. et al. Ann. Intern. Med. (2013)

For any information/question: [email protected]

mailto:[email protected]

REFERENCES

Oxford Desk Reference Nephrology. Barratt J, Harris K &

Topham P (ed) Oxford University Press 2009.

Comprehensive Clinical Nephrology, 3rd ed. Feehally J, Floege J

& Johnson RJ (ed) Mosby Elsevier 2007.

Fundamentals of Renal Pathology (Stand-Alone CDRom). Fogo

AB, Bruijn JA, Cohen AH, Colvin RB, Jennette JC (ed) Springer

2008.

Atlas de Pathologie Rénale. Noël LH (ed) Médecine-Sciences

Flammarion 2008.

Clinical Nephrotoxins, 2nd ed. De Broe ME, Porter GA, Bennett

WM, Verpooten GA (ed) Kluwer Academic Publishers 2003.

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