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ESP Nephropathology WG
Slide Seminar (Krakow 2010)
“DRUGS AND KIDNEY”
Case No. 6
Dušan Ferluga
Institute of Pathology, Faculty of Medicine
University of Ljubljana, Ljubljana, Slovenia
Medical history (I)
of a 46-year-old woman
1974 (age 13) - Juvenile rheumatoid arthritis
1974-83
- Th: corticosteroids, gold, NSAID
1983 (age 22) - Overlapping SLE (5 ARA: butterfly rash,
arthritis, ANA pos, a-dsDNA pos 0.98,
proteinuria 1.1 g/d)
1st renal biopsy Class I, ID mes ++, sed +, sep+-/+
1983-89
- Th: Cyclophosphamide pulses,
corticosteroids
Remission of most symptoms, release
of laboratory findings
Recurrent deep vein thrombosis assoc.
IgG aCL in high titer
Dg. APS Th warfarin
1st kidney biopsy in 1983 (age 22)
Medulla and cortex with 9 glomeruli
ISN/RPS Class I (min mes lupus nephritis)
IA 0, IC 0
IF: »full-house« glom mes ID
EM: dense deposits mesangial/paramesangial ++,
sparse, segmental sed+, sep+-/+,
endothelial TRI myxovirus-like +,
no myelin-like cytoplasmic inclusions
1st kidney biopsy
1st kidney biopsy – EM
Medical history (II)
of a 46-year-old woman
1989 (age 30) - ANA pos, a-dsDNA low pos 0,45
2000 (age 41) - Positive skin biopsy band test by DIF
Urinalysis: norm
2001 (age 42) - ANA pos 1:640, ENA pos HTE 1,
a-dsDNA pos 0.86, IgG aCL pos (>30)
Th: cyclosporin (RR) replaced
methothrexate (side effects) replaced
2001-2006
- Th: chloroquine 250 mg/d (cumul. 413 g)
Clinical / laboratory findings
at 2nd biopsy
2006 (age 46) - Lab parameters of inflamm (SR, CRP) low
Reduced joint swelling and pain,
ARA criteria not fulfilled
(SLE in remission?)
S-creatinine 150 µmol/L ()
Urinalysis: proteinuria 0.25-0.5 g/d,
mild erytrocyturia and leukocyturia
2nd renal biopsy
2nd kidney biopsy in 2006 (age 46)
Medulla and cortex with 14 glomeruli
 LM: Widespread global (8/14) and segmental (1/14)
glomerulosclerosis
Focal (25%) interstitial fibrosis and tubular atrophy
Moderate arteriosclerosis and arteriolosclerosis
 IF: Glom mesangial IgG, IgM and C3 in traces ()
 EM: Traces of dissolved mesangial and subepithelial
deposits. No features of active lupus nephritis.
A variety of cytoplasmic inclusions in renal cells
 Dg.: 1. Class I lupus nephritis resolved (Class IVG (C)?)
2. FSGS, coincidental drug-induced?
2nd kidney biopsy
2nd kidney biopsy – EM
2nd kidney biopsy – EM
2nd kidney biopsy – EM
2nd kidney biopsy in 2006 (age 46)
CONCLUSION
 EM: Numerous myelin- and zebra-like lamellar
cytoplasmic inclusions, irregularly distributed in
variety of renal cells are ultrastructural features
compatible with those of Fabry disease, particularly
in heterozygous woman.
However, additional findings of peculiar curvilinear
bodies, convincibly demonstrated in vascular
smooth muscle cells and one of the glomerular
mesangial cells are highly suggestive of iatrogenic
chloroquine-induced renal phospholipidosis.
Skin biopsy – EM
First skeletal muscle biopsy – EM
Second skeletal muscle biopsy – EM
(6 months after chloroquine withdrawal)
Skin and skeletal muscle biopsies
(age 46)
 EM: Myelin-like and occasionally zebra-like lamellar
cytoplasmic inclusions were demonstrated in the
sarcoplasm of myofibers and in a variety of cells in
the skin biopsy.
Associated curvilinear cytoplasmic bodies, present
in abundance in the sarcoplasm of myofibers and to
lesser extent in the vascular smooth muscle cells.
Complete clearance of lamellar inclusions but
remnants of curvilinear bodies in follow-up skeletal
muscle biopsy six months after chloroquine
withdrawal.
Final diagnosis:
IATROGENIC CHLOROQUINE-INDUCED
SYSTEMIC PHOSPHOLIPIDOSIS
mimicking Fabry disease
Arguments confirming final diagnosis:
 Curvilinear cytoplasmic inclusions in addition to
myeloid and zebra bodies
 Slowly progressive renal insufficiency and biopsy
proven nephrosclerosis could much easier be
ascribed to chloroquine in cumulative dose of
413 g than to SLE being in remission
 Considerable improvement of renal function and
clearance of lamellar bodies from skeletal muscle after
6 months of discontinuation of chloroquine therapy
 Absence of ultrastructural features of Fabry disease in
the first renal biopsy
 Lack of family history of Fabry disease
 Peripheral leukocyte testing for -galactosidase A
level within normal range and genetic analysis
excluding mutation of -galactosidase A gene
Chloroquine side-effects in humans
retinopathy (1959), neuromyopathy (1963),
cardiomyopathy (1977), nephropathy (2003) –
iatrogenic phospholipidosis shared with more
than 50 drugs with different therapeutic actions
but all cationic, amphiphilic and lysosomotropic
Literature on chloroquine-induced
phospholipidosis
Case
reports
Underlying
Disease
Chloroquine
Time Cumm
Müller-Hocher
J et al, 2003
Sjögren
syndrome
11 mo
Albay D et al,
2005
Bracamonte
ER et al, 2006
Wojwodt A
et al, 2007
Lamellar
bodies
Curvilin
bodies
Prot
(g/d)
S-Creat
(mg/dL)
51 g
+++/+
+
cell type?
0
1.0-2.1
Rheum
arthritis
18 mo 130 g
+++/+
0
(muscle
biopsy+)
traces
2.2
Undefined
autoimm
disease
10 yrs
intermitent
+++/+
0
1.2
1.3
SLE
Several
years?
+++/+
0
2
CCr
64ml/min
Tentative mechanisms involved in pathogenesis
of chloroquine-induced phospholipidosis
• Adsorption to plasma membrane and accumulation
in lysosomes
• Formation of amphiphilic cationic drug–polar lipid
complexes resistant to digestion
• Inhibition of lysosomal enzyme activities through
drug-induced increase of pH
• Direct drug induced strong but reversible inhibition
of lysosomal phospholipases A and C and possibly
other hydrolases
Patients
(Kidney biopsy files 1987-2007)
25 pts, mostly SLE, on chloroquine 250 mg/d (1day – 8yrs)
___________________________________________
Chloroquine treatment
Renal
lipidosis
No. of
pts
Duration
Cummulative
Withdrawn
before biopsy
Yes
6
(24%)
11 days – 4.5 yrs
5.3 – 413 g
0
Suspected
3
(12%)
37 days – 10 mo
11.7 – 79 g
0
No
2
(8%)
1 day – 2 days
0.5 – 1.0 g
0
No
14
(56%)
27 days – 5 yrs
9.3 – 460 g
3 mo – 8 yrs