Chronic Calcineurin Inhibitor Nephrotoxicity: Myth or Reality?
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1 Chronic Calcineurin Inhibitor Nephrotoxicity: Myth or Reality? Aji Djamali, MD Associate Professor of Medicine and Surgery Division Chief Nephrology University of Wisconsin School of Medicine and Public Health
2 CNIs, Mechanism of Action Samaniego, Becker, Djamali, Nature Clin Pract Nephrol, 12, 2006 VOL 2 NO 12
3 Calcineurin Inhibitors are the backbone of maintenance immunosuppression 100% 90% 80% 70% 60% 50% 40% 30% SRL CsA TAC 20% 10% 0% Heart Intestine Kidney KP Liver Lung PAK PTA 2008 OPTN / SRTR Annual Report
4 100% 66% N Engl J Med 2003;349:
5 CsA associated with a 25% greater risk of ESRD than TAC
6 CNI nephrotoxicity: pathogenesis Normal glomerulus Glomerulus + CsA P < HTN Prevalence 3M 1 yr 2 yr CsA TAC Adapted from English et al. Transplantation 1987:44:135 Campistol et al. Nephrol Dial Transplant 2004; 19 (S3): 62-6
7
8 Reducing Risk Exposure to Immunosuppressive drugs Avoidance Withdrawal Minimization
9 Minimizing Strategies Ekberg, Halloran et al, Elite Symphony Trial, NEJM 2007 P<0.05 CsA, MMF, P KTR N=1645 Daclimuzab CsA, MMF, P Daclimuzab TAC, MMF, P Daclimuzab SRL, MMF, P P<0.05
10 Avoidance: Belatacept egfr higher than CsA in BENEFIT and BENEFIT-EXT trials 80 BENEFIT-EXT 80 BENEFIT Mean GFR, ml/min/1.73 m 2 (95% CI) Belatacept CsA Belatacept CsA Month Month Durrbach A, et al. ATC Abstract.100.
11 Withdrawal: Everolimus-based, CNI-free regimen in recipients of de-novo kidney transplants: an open-label, randomized, controlled trial Budde K et al, Lancet 2011; 377:
12 Identifying specific causes of kidney allograft loss Loss of Functioning Graft 31% 16% 5% 12% 36% Acute Rejection Glomerular Disease IFTA Medical/Surgical Unknown Specific cause identified in 80% CNI only in 1% El Zoghby et al, AJT, 2009; 9:
13 Specific Causes of Kidney Allograft Loss Polyoma Virus Nephropathy ABMR Medical/ Surgical Conditions Glomerulonephritis Mixed Rejection Probably ABMR Sellarés J 2011, et al. Am J Transplant.12:
14 CNI nephrotoxicity was associated with improved Graft Survival Long term Deterioration in Kidney Allograft Function (DeKAF) Study Gaston et al, Transplantation 2010;90: 68 74
15 The Histology of Solitary Renal Allografts at 1 and 5 Years After Transplantation Stegall et al, AJT 2011; 11:
16 Study Conclusion Stegall et al, AJT 2011; 11:
17 The Discrepancies between Mayo and Australian Studies % lesions in protocol biopsies at 5 years 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 90% 66% 17% 19% ci 2 ah 2 Nankivell Stegall SPK vs. Solitary Kidneys Bladder drained Infections Volume Contraction CsA vs. TAC Different rejection rates and dosing Mayo Low Risk 95% Caucasian 80% LD DD better GFR than LD No ECD
18 Kidney Allograft Fibrosis and Atrophy Early After Living Donor Transplantation LD DD Banff 97 scores of 0 (open bar), 1 (stippled bar), 2 (stripped bar), 3 (black bar). Top: LD kidney recipients; Bottom: DD kidney recipients Cosio et al, AJT 2005; 5:
19 Study Conclusion Cosio et al, AJT 2005; 5:
20 Chronic Kidney Disease Stage Progression in Liver Transplant Recipients 30.00% 25.00% 25% 20.00% 18% 18% 15.00% 10.00% 8% UW SRTR Ojo 5.00% 0.00% 3% 5 years 10 years 20 years LaMattina et al, Clin J Am Soc Nephrol 6: , 2011
21 Summary Part I Chronic CNI nephrotoxicity may be less prevalent in the new era of immunosuppression TAC > CsA Lower doses Alternative immunosuppressants However, CNIs are still the backbone of Immunosuppression
22
23 Working Hypothesis CNI Nox2 Intrarenal Hypoxia Fibrosis
24 Nox2 O 2 p p22 p47 p p Nox 2 p40 p67 Rac GTP NADPH
25 enos, inos (nitric oxide synthase enzymes) NO (nitric oxide) NADPH oxidase (Nox) SODs Superoxide Dismutase Catalase O 2 (oxygen) e - e - O 2 - (superoxide anion) H 2 O 2 (Hydrogen peroxide) H 2 O + O 2 (water + oxygen) ONOO - (Peroxynitrite) Fe +++, Cu ++ (Fenton reaction) Glutathione (GSH) GPX (Glutathione peroxidase) Lipid peroxidation (e.g. MDA) Protein Nitration (e.g. nitrotyrosine) OH (Hydroxyl radical) H 2 O (water) Reactive oxygen species (ROS) Enzymes involved in the OS pathway
26
27 Cell culture Studies
28 Calcineurin inhibitors increased Nox2 mrna in NRK52E cells 8 * *p<0.05 compared to no treatment 7 Fold change compared to control * * * * * 1 0 CsA 1 μm CsA 10 μm TAC 1 μm TAC 10 μm TGF-β 10 ng/ml TGF-β 20 ng/ml Djamali et al, AJT 2012; 12:
29 CsA increased Nox2 and TGF-β1-related proteins in NRK52E cells TGF-β1 20 ng/ml CsA 1 μm CsA 10 μm a-immunoblots b-protein:β-actin normalized ratios *p<0.05 compared to Rx No Rx 0.8 TGF-β 0.4 * * * CsA 1 CsA 10 0 * Nox-2 p-p38mapk p-smad3 p-nfκb α-sma * Djamali et al, AJT 2012; 12:
30 Calcineurin inhibitors dedifferentiated epithelial NRK52E cells No treatment CsA 1 μm a b c CsA 10 μm Spindle-shaped cells TAC 1 μm TAC 10 μm d e Spindle-shaped cells Djamali et al, AJT 2012; 12:
31 CsA-induced EMT and Nox2 protein expression were TGF-β1 dependent a No Treatment CsA 10μM b (e) Nox2 immunoblot Wild Type TGF-β KO NoRx CsA NoRx CsA Wild-type Nox2 58kd β-actin 42kd Spindle-shaped cells (f) Protein:β-actin ratio TGF-β1 KO c d * * P < 0.05 compared to all 40 0 No Rx CsA No Rx CsA Wild Type TGF-β KO Djamali et al, AJT 2012; 12:
32 Nox2 and CsA nephrotoxicity: animal models Vehicle Fisher 344 CsA 15 mg/kg/d CsA + Apocynin 16 mg/kg/d CsA + DPI 0.5 or 1 mg/kg/d 1 month Djamali et al, AJT 2012; 12:
33 Renal Function Scr (mg/dl) at 1 month p<0.05) Olive Oil Fisher 344 CsA (15mg/kg/24h) n=8 10 in each group Djamali et al, AJT 2012; 12:
34 Characteristics of chronic CsA nephrotoxicity a No CsA b High dose CsA Arteriolar hyalinosis Trichrome PAS Afferent arteriole c d Striped fibrosis Djamali et al, AJT 2012; 12:
35 a Fibrosis and Nox2 in the Rat Model of CsA Nephrotoxicity Vehicle CsA b Trichrome Striped Fibrosis α-sma and Nox2 double-stain c α-sma Nox2 d Nox2 α-sma Djamali et al, AJT 2012; 12:
36 Inhibition of Nox2 was associated with reduced CsA-induced Fibrogenesis (a) Immunoblots (b) Protein levels normalized to GAPDH CsA 15 mg/kg/24h Apo 16 mg/kg/24h DPI 0.5mg/kg/24h DPI 1 mg/kg/24h * p < 0.05 CsA compared to all other groups ** p < 0.05 CsA compared to all except Apocynin-treated group 58kd Nox2 α-sma 42kd Nitrotyrosine 60kd P-smad3 52kd Densitometric units 140 NoRx * * * ** ** CsA 15mg/kg/24h Apo 16mg/kg/24h DPI 0.5mg/kg/24h DPI 1mg/kg/24h T-smad3 GAPDH 52kd 37kd 20 0 Djamali et al, AJT 2012; 12:
37 Inhibition of Nox2 was associated with reduced picrosirius staining a NoRx f-digital Image Analysis of Picrosirius * Total Signal (OD) p = 0.02 vs. NoRx p = 0.02 vs. CsA + Apo p = vs. CsA + DPI 0.5 p = vs. CsA + DPI NoRx CsA CsA+Apo CsA+DPI 0.5 CsA+DPI 1.0 b CsA 15mg/kg/24h c CsA + Apo 16mg/kg/24h d CsA + DPI 0.5mg/kg/24h e CsA + DPI 1mg/kg/24h Djamali et al, AJT 2012; 12:
38 CsA Nephrotoxicity was reduced in Nox2 -/- mice a-wild Type + CsA 30mg/kg/24h b-nox2 -/- + CsA c-trichrome Staining Marker Area (pixels) p<0.05 Interstitial fibrosis 0 WT KO d-immunoblots 90 WT Nox2 -/- 80 * p< Nox2 58kd 60 * 50 α-sma 42kd * HNE 75kd 20 GAPDH 37kd 10 0 Nox2 HNE α-sma Densitometric units e-protein normalized to GAPDH * WT Nox2-/- Djamali et al, AJT 2012; 12:
39 Liver Transplant Recipients with Biopsy Proven Chronic CNI Toxicity Number of Patients 15 Year of Transplant Age at transplant (years) 54.5±2.6 White Race 13 Male Gender 8 Time to Biopsy (years) 5.4±0.8 Diabetes 8 HTN 14 Serum creatinine at biopsy 1.5±0.08 Proteinuria on UA > 1+ 5 Last serum creatinine 1.8±0.1 Follow up after biopsy (years) 2.5±0.3 Djamali et al, AJT 2012; 12:
40 Nox2 was increased in human kidneys with CNI-induced fibrosis a-control Human Kidney b-chronic TAC Nephrotoxicity c-chronic CsA Nephrotoxicity Nox2 α-sma α-sma α-sma Nox2 Marker Area (pixels) * d-digital Image Analyses for Nox2 and α-sma * ** ** asma Nox2 * Nox2 p = vs. Tac p = vs. CsA * α-sma p = vs. Tac p = vs. CsA ** Nox2 p = 0.12 vs. CsA ** α-sma p = vs. CsA Control Tac CsA Djamali et al, AJT 2012; 12:
41 CNI Nox2 Intrarenal Hypoxia Fibrosis
42 Summary Part II TAC and CsA increased Nox2 expression in nonphagocytic cells Nox2 expression increased in human and animal model of chronic CsA induced fibrosis Inhibition of Nox activity associated with Reduced CsA induced fibrosis Prevention of CsA induced hypoxia/hypoperfusion Nox2 is involved in pathogenesis of CNIinduced renal injury
43 Conclusions There is no specific biomarker of chronic CNI nephrotoxicity TAC and CsA at high dose can be nephrotoxic Animal studies support this evidence However, in transplant kidneys The specific role of chronic CNI nephrotoxicity has yet to be defined Balancing act: avoid chronic rejection vs. chronic drug toxicity TAC better than CsA for GFR and maybe fibrosis
44 Acknowledgements Nephrology Lab Nancy Wilson Schlei, PhD Shannon Reese, MS Lynn Jacobson, BS Omeed Hafez Zaheer Akhtar Pierre Emmanuel Chammas Ling jin Huang Radiology Liz Sadowski, MD Sean Fain, PhD Funding R01 NIDDK
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