Hasan Fattah 4/30/2013

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1 Hasan Fattah 4/30/2013

2 49 yo hispanic male, ho HIV(CD4 229), currently on HAART, course c/b AIDS, Presents with two days ho fever, SOB, blood tinged sputum, and visible hematuria. ROS: no skin rash, joint pain, UR sx, other GI/GU sx. PMH: HIV c/b PCP/TB/MAC/COPD(on home o2), lung empyema s/p R thoracotomy 12/2010, pulmonary AVM, pseudomonas vertebral OM 5/2012, IVDA. Meds: truvada, kaletra, methadone. Heavy ex-smoker No personal or family ho renal stones.

3 Exam: Vitals: T: bp: 127/85 p: 82 po2: 99 nc. Gen: NAD. Chest: right ribcage bandaged, healing granular tissue, left basilar rales. CV: regular, no murmurs, or rub Abd: soft. NT Ext: pitting edema 2+, no skin rash

4 Labs: BMP BUN Cr Na K co2 10/18/ /11/ /22/ URINE PH PRO BLOOD WBC RBC 5/11/ /13/ TRACE NEGATIVE /11/

5 WBC: 15 H/H: 12/36 plts: 157 Uric acid: 5.6 Ca: 8.5 po4: 4 alb: 3.7 Spot protein/cr: 7 g/g LDH/RF: WNL Anti-GBM/ANCA/ANA/ds DNA/hep B, and C NEG C3/C4: WNL Renal US: normal size, no hydro, no stones

6 Renal pathology: Mild mesangial expansion and 3/9 glomeruli show cellualr crescents, no TMA. IF: 3+ Ig A, faint kappa/lambda/c3/igg EM: frequent mesangial deposits

7 Conventional therapy tolerability.. PTKI

8 Distribution of protein tyrosine kinase genes in the human genome

9

10

11

12 Mechanism of action of tyrosine kinase International Journal of Medical Sciences

13 The ATP competitive inhibitors are target of choice Int J Med Sci 2004

14

15 Imatinib targets: 1. c-abl. 2. PDGFR. 3. stem cell growth factor receptor (c-kit). 4. discoidin domain receptor (DDR) 1 and 2 5. macrophage colony stimulating factor receptor (c-fms) 6. lymphocyte-associated kinase (lck).

16 Murine studies Animal Reported Imatinib effectivness: Crescentic GN. mesangial proliferative GN. chronic allograft nephropathy diabetic nephropathy lupus nephritis unilateral obstructive nephropathy cryoglobulin-associated (MPGN) anti-glomerular basement nephritis

17 Despite promising results with the use of imatinib in murine models of kidney disease, only two case reports have described its use in human kidney disease.

18 Imatinib s immunomodulatory effects. Wallace E, and Gewin L JASN doi: /asn by American Society of Nephrology

19 Schematic representation of Kit-mediated PI 3- kinase and Src family kinase signaling in bone marrow-derived mast cells The EMBO Journal (1998)

20 Targeted Oncology Springer-Verlag 2007

21 Imatinib decreases cryoglobulin levels and serum Ig repertoire in TSLP-Tg mice by American Society of Nephrology Iyoda M et al. JASN 2009;20:68-77

22 Imatinib attenuates glomerulonephritis in TSLP-Tg mice. Iyoda M et al. JASN 2009;20: by American Society of Nephrology

23 Morphometric data from mice receiving 4 wk of imatinib treatment beginning at day 90 Parameter WT TSLP-Control TSLP-Imatinib % GTA occupied by 6.25 ± ± ± 0.66 silver-stained matrix Cell number/glomerular ± ± ± 1.91 cross-section % GTA occupied by ± ± ± 0.68 collagen type IV stained matrix % GTA occupied by α ± ± ± 0.24 SMA expressing cells GTA occupied by Mac- 2 expressing cells (μm 2 ) 4.98 ± ± ± 51.98

24 In summary, animal models suggest that imatinib affects the B cell immune response through decreased B cell development and function, and clinical studies suggest that imatinib dampens B cell production of antibodies.

25 Fibrogenic pathways targeted by imatinib. Wallace E, and Gewin L JASN doi: /asn by American Society of Nephrology

26 Long- and short-term treatment with imatinib attenuates the development of chronic kidney disease in experimental anti-glomerular basement membrane nephritis Nephrol Dial Transplant (2013) 28:

27 Experimental design. Iyoda M et al. Nephrol. Dial. Transplant. 2013;28: The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

28 Not only long-term but also short-term treatment with imatinib reduced proteinuria in the rats with NTS-N. Iyoda M et al. Nephrol. Dial. Transplant. 2013;28: The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

29 Effects of imatinib on renal function, body weight and kidney weight by the study group Group Ccr (ml/h) Cr (mg/dl) WKY-NTS ( ) (N = 7) day 50 WKY-NTS (+) (N = 6) day7 Long-term treatment a day 50 WKY-vehicle (N = 8) WKYimatinib (N = 8) Short-term treatment b day 50 WKY-vehicle (N = 10) WKYimatinib (N = 10) Body weight (g) Kidney weight (g) ± ± ± ± ± ± ± ± ± 4.14 ## 0.39 ± 0.01 ## ± 4.61 # 2.09 ± 0.04 ## ± 3.83* 0.28 ± 0.01** ± ± 0.03*** ± 7.55 # 0.40 ± 0.05 ## ± 3.30 # 1.91 ± 0.07 ## ± 7.85* 0.32 ± 0.02* ± ± 0.05*

30 Morphological evaluation of glomerular sclerosis and tubulointerstitial damage at the end of study Group Glomeruloscleros isscore (0 4) WKY-NTS( ) (N = 7) day Long-term treatment a day 50 Tubulointerstitial damage score (0 5) WKY-vehicle (N = 8) 2.43 ± ± 0.20 WKY-imatinib (N = 8) 1.24 ± 0.38** 2.57 ± 0.61** Short-term treatment b day 50 WKY-vehicle (N = 10) 2.01 ± ± 0.52 WKY-imatinib (N = 10) 1.28 ± 0.24* 2.70 ± 0.60*

31 Effects of imatinib on profibrogenic genes in the study groups. Iyoda M et al. Nephrol. Dial. Transplant. 2013;28: The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

32 Effects of imatinib on TGF-β1 protein synthesis in the study groups. Iyoda M et al. Nephrol. Dial. Transplant. 2013;28: The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

33 imatinib showed marked renoprotective effects: suppressed proteinuria improved renal function as evaluated by Ccr and serum Cr levels attenuated the development of glomerulosclerosis and tubulointerstitial injury reduced the expression of collagen type I and TGF-β in renal cortex

34 imatinib could limit: the progression of GN to end-stage renal failure even if used for only a short period at an early stage of GN. may be beneficial in terms of cost-effectiveness and reduction of adverse effects in comparison to continuous and long periods of treatment.

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