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ESP Nephropathology WG Slide Seminar (Krakow 2010) “D RUGS AND KIDNEY ” Case No. 6

ESP Nephropathology WG Slide Seminar (Krakow 2010) “D RUGS AND KIDNEY ” Case No. 6. Du š an 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

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ESP Nephropathology WG Slide Seminar (Krakow 2010) “D RUGS AND KIDNEY ” Case No. 6

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  1. 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

  2. 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

  3. 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

  4. 1st kidney biopsy

  5. 1st kidney biopsy – EM

  6. 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)

  7. 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

  8. 2nd kidney biopsy in 2006 (age 46) Medulla and cortex with 14 glomeruli • LM: Widespread global (8/14) and segmental (1/14) glomerulosclerosisFocal (25%) interstitial fibrosis and tubular atrophyModerate 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?

  9. 2nd kidney biopsy

  10. 2nd kidney biopsy – EM

  11. 2nd kidney biopsy – EM

  12. 2nd kidney biopsy – EM

  13. 2nd kidney biopsy in 2006 (age 46) CONCLUSION • EM: Numerous myelin- and zebra-like lamellarcytoplasmic 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.

  14. Skin biopsy – EM

  15. First skeletal muscle biopsy – EM

  16. Second skeletal muscle biopsy – EM (6 months after chloroquine withdrawal)

  17. 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.

  18. Final diagnosis:IATROGENIC CHLOROQUINE-INDUCED SYSTEMIC PHOSPHOLIPIDOSIS mimicking Fabry disease

  19. 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

  20. 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

  21. Literature on chloroquine-induced phospholipidosis

  22. 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

  23. Patients(Kidney biopsy files 1987-2007) 25 pts, mostly SLE, on chloroquine 250 mg/d (1day – 8yrs) ___________________________________________ Chloroquine treatment

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