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Allograft Nephropathy and Cardiovascular Disease: Important for Graft and Patient Survival – Implications for Diagnosis and Treatment Matthew R. Weir,

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Presentation on theme: "Allograft Nephropathy and Cardiovascular Disease: Important for Graft and Patient Survival – Implications for Diagnosis and Treatment Matthew R. Weir,"— Presentation transcript:

1 Allograft Nephropathy and Cardiovascular Disease: Important for Graft and Patient Survival – Implications for Diagnosis and Treatment Matthew R. Weir, M.D. Professor and Director Division of Nephrology University of Maryland School of Medicine

2 Leading Causes of Graft Failure CVD (also known as death with functioning graft) Allograft Nephropathy Are they related?

3 Overview Cardiovascular risk profile in the kidney transplant recipient vs the general population Renal autoregulation and microalbuminuria Risk reduction strategies: focus on blood pressure, cholesterol and glucose Optimal immunosuppression strategies Conclusions

4 Cardiovascular disease is much more common among renal transplant recipients compared to the general population The greater incidence of CVD is not entirely explained by traditional risk factors, (blood pressure, cholesterol, glucose). Thus, other factors may be involved (immunosuppression, rejection, infection?) Kasiske BL et al. J Am Soc Nephrol 2000;11:

5 Older Younger --Diabetic---Non-Diabetic-Diabetic -Non-diabetic Smoker Non-Smoker year survival without IHD Observed and Expected Risk for Ischemic Heart Disease after Renal Transplantation

6 This raises even more questions about the rigor of our approach to CV risk reduction in transplant patients, particular if they have diabetes!

7 Cardiovascular Risk Profile of the Renal Transplant Recipient Hypertension Diabetes Dyslipidemia Renal Disease

8 The Transplant Kidney Optimal GFR ml/min, less in situations of ischemia/reperfusion injury, marginal donors, nephrotoxic drugs or rejection Risk for hyperfiltration injury? Pre-existing milieu of hypertension, diabetes and vascular disease

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10 Unmet Need We need better long-term immunosuppression strategies to avoid the metabolic stresses of diabetes, hypertension and dyslipidemia on both the heart and the kidney and the vascular tree Biggest focus: corticosteroids calcineurin inhibitors (CNI)

11 Corticosteroid Withdrawal Feasible, particularly with newer, more effective drugs and biologicals Will result in fewer metabolic consequences Not for everyone! Perspective: how often does 2.5 – 5 mg/day prednisone cause problems? Avoidance protocols more successful than tapering: chronic use may condition immune system and increase the risk for rejection.

12 CNI Withdrawal or Minimization a more practical issue define risk: benefit ratio metabolic improvement cyclosporine: BP, cholesterol, glucose, kidney function tacrolimus: glucose, kidney function need to be sure no T cell- or antibody- medicated rejection

13 Renal function as an endpoint: a historical perspective 1978: Opelz et al examined all primary grafts at 105 centers between 1971 and 1976 (n ~ 4000) Renal function at all time points (d1, wk1, m1) was correlated with graft survival 33% of graft failed < 30 days and 1 year graft survival 40-50%

14 Decreased Renal Function is a Strong Risk Factor for Cardiovascular Death following Renal Transplantation USRDS Registry –First Transplants – –Adults –Multi-organ Transplants excluded All with functioning graft at one year post transplant (Scr≤4mg/dl) Meier-Kriesche, Kaplan et al. Transplantation 2003

15 <1.3 Scr /RR months post-transplant % Cardiovascular death free survival Cardiovascular Death Events in KTX by SCr at One Year Post Transplant Cardiovascular Death Events in 48,832 KTX by SCr at One Year Post Transplant Meier-Kriesche, Kaplan et al. Transplantation

16 Conclusions independent association between decreased renal function and increased risk for cardiovascular death exists The degree of renal failure was strongly correlated to the risk for cardiovascular death

17 Functional cadaveric renal allograft survival (censored for death with a functioning graft) after the first year following transplantation, by year of transplant. Hariharan S. NEJM 2000; 342:605. Era of 1988 to 1994, both acute rejection rates and graft survival rates were improving Better intercept or improving slope? Renal function is a natural candidate for a surrogate marker of graft loss

18 Distribution of Serum Creatinine at 1 year post deceased donor kidney transplantation (donor age<50 yrs) Transplant Year < >2.5 NA N = 54,388 Hariharan S. NEJM 2000; 342:605. %

19 ALTERNATIVE MECHANISMS FOR EARLY KIDNEY GRAFT FAILURE Ccr Time Ccr at return to dialysis Good Function Accelerated Slope Reduced Intercept

20 Transplant year Cumulative Percent SLOPE (ml/min/month) <= The % of patients with a negative slope of GFR after 6m has decreased Gourishankar, JASN 2003

21 Transplant year Cumulative Percent SLOPE (ml/min/month) <= What is graph for the current population? Gourishankar, JASN 2003

22 A shift in conceptual frameworks: challenging traditional assumptions 1.Early function (slope) predicts late function (slope) ie. worse early function results in more aggressive deterioration of function 2.Graft loss is inevitable following kidney transplant as the average slope is decreasing

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24 There is no relationship between early and late slope The average early slope was ± 9.66 ml/min/year and subsequent slope was ± 9.81 ml/min/year Gourishankar and Hunsicker 2007 ASN SU-PO438, 475, 219

25 Stable over the years; possible recent improvement % with long term positive slope increased to 50% of recipients experiencing slopes >=0 ml/min/yr

26 Conclusions 1.In over half of kidney and kidney-pancreas transplant recipients, the slope is less negative than -1 ml/min/year or even positive. 2.These data show that the rate of loss of kidney function (GFR) for the first 3 years following kidney and kidney- pancreas transplant does not predict the subsequent rate of loss. 3.The loss of GFR early or late following kidney and kidney-pancreas transplantation is not inevitable and any loss of GFR should be explained.

27 Summary 1.Renal function can be used as a new endpoint in kidney transplantation interpreted in the form of slopes and intercepts 2.The majority of the “action” occurs after 6 months; baseline factors are poorly predictive of long-term outcomes 3.The stability of renal function after kidney transplantation is improving 4.Loss of graft function is not inevitable following kidney transplantation

28 Renal Autoregulation How low should you go? What drugs should you use? Short-term, long-term concerns?

29 Glomerular Structure Mesangial Cell Endothelial Cell Capillary Loop Afferent Arteriole Juxtaglomerular Apparatus Efferent Arteriole

30 Implications of Microalbuminuria or Proteinuria?

31 Schematic of Events With Microalbuminuria/Proteinuria Decreased nephron mass Glomerular-capillary hypertension Increased filtration of plasma proteins Excessive tubular reabsorption of protein Release of vasoactive and inflammatory substances into the interstitium Glomerulosclerosis and fibrosis  Mechanical stretch and strain  Activation angiotensin II and transforming growth factor ß1 Proteinuria Increased synthesis of Type IV collagen Fibroblast proliferation Interstitial inflammatory reaction

32 Cardiovascular Events by Degree of Albuminuria in HOPE Gerstein HC et al. JAMA. 2001;286: Incidence (%) All participants With diabetes Without diabetes Microalbuminuria threshold Albumin/Creatinine Ratio Deciles 1 and

33 Multivariate Hazard Ratios for Primary Outcome in HOPE HOPE Study Investigators. N Engl J Med. 2000;342: Microalbuminuria CAD Diabetes Creatinine  1.4 mg/dL Male WHR (0.1) Age (1y) Ramipril Hazard Ratio

34 Microalbuminuria Resets the Focus on CV Risk Reduction Strategies BP <130/80 mmHg Evaluate lipids Extinguish microalbuminuria Reduction in dietary salt/saturated fat Intensify glycemic control ASA

35 Opelz G, et al Kidney Int 1998;53:

36 Allograft Nephropathy Hypertension/proteinuria/declining kidney function are the hallmarks of this disease process Need for specific antihypertensive, antiproteinuric approaches? Modification of immunosuppression

37 Chronic Rejection of Renal Allografts Impact of Early Events Acute Rejection Ischemia/Reperfusion CMV and Other Infections Donor Factors Adhesion Molecules, Cytokines, Growth Factors INJURY LOSS OF NEPHRON MASS CHRONIC GRAFT DYSFUNCTION

38 Chronic rejection Effector mechanisms Antibodies Brain death Ischemia/reperfusion injury Inadequate renal mass (donor age, gender, race, organ size) Hypertension and hyperlipidemia Drug nephrotoxicity CMV, other infections Cytokines Growth factors Cytokines Costimulation Allorecognition HLA matching Acute rejection Ongoing subclinical immunologic injury Alloantigen-Dependent Mechanisms Alloantigen-Independent Mechanisms B Cell T Cell Macrophage APC Endothelium

39 Lumenal Obliteration Due to Vasculopathy in Chronic Allograft Nephropathy

40 Tubulointerstitial Fibrosis and Scarring in Chronic Allograft Nephropathy

41 Calcineurin Inhibitors CSA vs FK Mechanism of Action Calcineurin inhibition Sympathetic nervous stimulation Nephrotoxicity Glomerular hemodynamics Salt sensitivity

42 Hypocellular lesions in areas of fibrosis Apoptosis > > Proliferation interstitial cell proliferation followed by Apoptosis  Renal ischemia and injury  TG F-  ?  apoptosis  extracellular matrix deposition.  Ang II Direct effect  ET-1  Sympathetic tone  Thromboxane A 2  NO  Prostaglandins  Prostacyclins CsA Vasoconstriction Calcineurin inhibitors and hemodynamic effects

43 University of Maryland Clinical Experience Trial in Patients with Allograft Nephropathy All patients were on triple immunosuppressive therapy: tacrolimus, mycophenolate mofetil and maintenance prednisone therapy. Patients were asked to discontinue tacrolimus after the first loading dose of sirolimus. Maintenance dose of sirolimus was adjusted to maintain goal trough level of 8-12 ng/ml. MMF used at 1g BID. Low dose prednisone mg QD. Wali RK, et al. Am J Transplant 2007;6:

44 Weir MR, et. al. Am J Nephrol 2004;24:

45 Demographics (n=125) Mean age in years (±SD)50.3 ± 14.2 Gender—Males, number (%)75 (60) Ethnic origin—number (%) Caucasians African American Others 56 (44.8) 67 (53.6) 2 (1.6) Cause of ESRD—number (%) Diabetes mellitus Hypertension Others 52 (41.6) 42 (33.6) 31 (24.8) Wali RK, et al. Am J Transplant 2007;6:

46 Demographics (contd) (n=125) Preemptive transplants -number (%)10 (8) Re-transplants - number (%)21 (16.8) Graft type - number (%) Cadaveric Living donor 93 (74.4) 32 (25.6) Induction therapy - number (%) Anti-CD25 84 (67.2) DGF - number (%)39 (31.2) Wali RK, et al. Am J Transplant 2007;6:

47 Pre / Post Conversion BUN & Creatinine Wali RK, et al. Am J Transplant 2007;6:

48 Changes in GFR (Nankivell Formula) after Conversion (Δ pre-post GFR ml/min) All pts. (n=125) Δ zero (n=7) Δ 1-15 ml/min (n=39) Δ >16 Ml/min (n=79) p Pre (mean ± SD) 24.8 ± ± ± ± Post (mean ± SD) 47.8 ± ± ± ± Wali RK, et al. Am J Transplant 2007;6:

49 Demographic Factors All (n=125) Δ 0 (n=7) Δ 1-15 ml (n=39) Δ >16 ml (n=79) p Age50.3± ±2151.7± ± Time post-tx (months) 5.4± ± ± ± Acute rejection 22 (17.6)1 (14)8 (20)13 (16).07 Follow up (months) 17.1 ± ± ± ± Wali RK, et al. Am J Transplant 2007;6:

50 Graft Loss during the follow up Percentage survival Δ>16 (n=79) Δ zero or less (n=7) Δ 1-15 (n=39) Kaplan-Meier graph for graft loss: Log Rank p=.0003 Wali RK, et al. Am J Transplant 2007;6:

51 Study Objective To evaluate combination mycophenolate mofetil (MMF) and sirolimus (SRL) as a calcineurin inhibitor (CNI)-free regimen for renal function preservation in renal allograft recipients

52 Trial Design MMF + tacrolimus MMF + cyclosporine MMF + tacrolimus MMF + cyclosporine MMF + sirolimus Post-randomization Patient screening and enrollment 1 year 2 years 30 – 180 DAYSPOST-TXPre-randomization

53 Dosing Regimens Mycophenolate Mofetil –1 to 1.5 g BID Sirolimus –2 to 10 mg loading dose –Maintain trough levels of 5 to 10 ng/mL Calcineurin Inhibitors/Corticosteroids –According to center practice

54 Key Inclusion Criteria Male/female, age 13 to 75 years Received a primary living or deceased donor renal allograft within the previous 30 to 180 days Maintained on MMF + CNI (TAC or CsA) with or without corticosteroids for 14 days pre-randomization

55 Key Exclusion Criteria Corticosteroid-resistant, biopsy-proven acute rejection or treated for acute rejection with antibody therapy within 90 days prior to randomizationCorticosteroid-resistant, biopsy-proven acute rejection or treated for acute rejection with antibody therapy within 90 days prior to randomization Corticosteroid-sensitive acute rejection 30 days prior to randomizationCorticosteroid-sensitive acute rejection 30 days prior to randomization >1 Biopsy-proven acute rejection prior to study entry>1 Biopsy-proven acute rejection prior to study entry SCr >2.5 mg/dL or CrCl 2.5 mg/dL or CrCl <30 mL/min (Cockroft- Gault) at study entry Total cholesterol levels >300 mg/dL or triglycerides >350 mg/dLTotal cholesterol levels >300 mg/dL or triglycerides >350 mg/dL

56 Endpoints PrimaryPrimary –Mean percent change from baseline to 12 months of measured GFR (cold iothalamate) SecondarySecondary –Biopsy-proven acute rejection at 12 months –Treatment failure at 12 months graft lossgraft loss deathdeath lost to follow-up/withdrawal of consentlost to follow-up/withdrawal of consent need to resume CNI therapyneed to resume CNI therapy dialysisdialysis premature withdrawal due to adverse eventpremature withdrawal due to adverse event –Safety All adverse events with a focus on hyperlipidemia and new onset diabetesAll adverse events with a focus on hyperlipidemia and new onset diabetes

57 RandomizedN=298 Patient Allocation (ITT)* MMF/CNIN=150 MMF/SRLN=148 TacrolimusWithdrawalN=122CyclosporineWithdrawalN=26 TacrolimusN=119CyclosporineN=31 *81% received tacrolimus and 19% received cyclosporine

58 MMF/CNI MMF/SRLN=148TotalN=150MMF/TACN=119 Sex, n (%)* Male Male Female Female 93 (63%) 55 (37%) 95 (63%) 55 (37%) 75 (63%) 44 (37%) Race, n (%)* Caucasian Caucasian 74 (50%) 74 (49%) 58 (49%) African American African American 48 (32%) 50 (33%) 40 (34%) Other Other 26 (18%) 26 (17%) 21 (18%) Age (years)* Mean  SD Mean  SD 48.7    12.5 Patient Demographics *P = NS for MMF/SRL vs MMF/CNI and for MMF/TAC vs MMF/CsA.

59 Baseline Characteristics MMF/CNI MMF/CNI MMF/SRLN=148TotalN=150MMF/TACN=119 Type of donor, n (%)* Living related Living related 41 (28%) 38 (25%) 29 (24%) Living unrelated Living unrelated 19 (13%) 21 (14%) 19 (16%) Deceased donor Deceased donor 88 (60%) 91 (61%) 71 (60%) PRA level (highest assessment), n (%)* 0% 0% 93 (63%) 91 (61%) 70 (59%) 1-19% 1-19% 31 (21%) 27 (18%) 24 (20%) >20% >20% 21 (14%) 27 (18%) 22 (19%) 22 (19%) Not known/missing Not known/missing 3 (2%) 5 (3%) 3 (3%) Time posttransplant to randomization* Mean ± SD, Days Mean ± SD, Days 113 ± ± 49 *P = NS for MMF/SRL vs MMF/CNI and for MMF/TAC vs MMF/CsA.

60 Induction Therapy, n (%) MMF/CNI MMF/SR L N=151TotalN=150 MMF/TA C N=119 Antithymocyte globulin 53 (35%) 44 (37%) Basiliximab 35 (23%) 44 (29%) 32 (27%) Daclizumab 20 (13%) 13 (9%) 8 (7%)

61 Mycophenolate Mofetil Dose MMF/SRL MMF/CNI Mean Dose (mg) ± SD Baseline N=140 N=139 Post-Randomization1 Month N=114 N=129 6 Months N=116 N= Months N=122 N=112

62 Tacrolimus Trough Levels Mean Tacrolimus Concentration ng/mL (± SEM) Baseline N=106 Post-Randomization2 Weeks N=92 6 Months N=97 12 Months N=88

63 Cyclosporine Trough Levels Mean Cyclosporine Concentration ng/mL (± SEM) Baseline N=30 Post-Randomization2 Weeks N=23 6 Months N=26 12 Months N=26

64 Sirolimus Trough Levels Mean Sirolimus Concentration ng/mL (± SEM) Day 7 N=123 Post-Randomization1 Month N=112 6 Months N= Months N=102

65 MMF/CNI MMF/SRL*N=148Total*N=150 MMF/TA C N=119 Biopsy-proven acute rejection rejection 10 (7%) 9 (6%) 7 (6%) Death 0 (0%) 3 (2%) 2 (2%) Graft loss 3 (2%) 4 (3%) 3 (3%) African Americans N=48*N=50*N=40 Biopsy-proven acute rejection rejection 4 (8%) 4 (10%) Efficacy Outcomes, n (%) *P = NS for MMF/SRL vs. MMF/CNI.

66 Mean % Change in Measured GFR Baseline to Month 12 N = 118N = Mean Percent Change ± SEM MMF/SRL MMF/CNI 7.8 Baseline GFR mL/min/1.7 m 2  SEM 59.5   P=

67 Mean % Change in Measured GFR, African Americans Baseline to Month 12 N = 39 Mean Percent Change ± SEM MMF/SRL MMF/CNI Baseline GFR (mL/min/1.7 m 2 )  SEM 61.6   3.9 P=

68 Other Renal Outcomes, Mean % Change MMF/CNIP-Value MMF/SRLN=148TotalN=150MMF/TACN=119 MMF/SRL vs Total Calculated GFR, mL/min Baseline, Mean±SEM Baseline, Mean±SEM 71.3± ± ±1.5 % change, baseline to month 12 (n) % change, baseline to month 12 (n) 6.2 (121) 1.1 (120) -0.3 (94) Serum creatinine, umol/L Baseline, Mean±SEM Baseline, Mean±SEM 121.1± ± ±8.0 % change, baseline to month 12 (n) % change, baseline to month 12 (n) 2.6 (122) 11.8 (120) 15.0 (94) Calculated creatinine clearance, mL/min Baseline, Mean±SEM Baseline, Mean±SEM59.7± ± ±2.0 % change, baseline to month 12 (n) % change, baseline to month 12 (n) 5.2 (122) -2.3 (120) -3.9 (94) 0.012

69 Urinary Protein/Creatinine Ratio MMF/SRLMMF/CNI All Patients* Total TAC WD TotalMMF/TAC Baseline, Median 25 th, 75 th percentiles (n) , 0.2 (123) , 0.2 (104) , 0.2 (129) , 0.2 (102) 12 Months, Median 25 th, 75 th percentiles (n) , 0.4 (106) , 0.4 (87) , 0.3 (110) , 0.2 (88) African Americans** Baseline, Median 25 th, 75 th percentiles (n) , 0.2 (40) , 0.2 (37) , 0.3 (44) , 0.3 (35) 12 Months, Median 25 th, 75 th percentiles (n) , 0.6 (34) , 0.6 (29) , 0.3 (40) , 0.2 (33) MMF/SRL vs. MMF/CNI: Baseline, P=NS; 12 Months, *P=0.096; **P=0.043.

70 MMF/CNI MMF/SRLN=148TotalN=150 MMF/TACN=119 Treatment failure* 44 (30%) 35 (23%) 30 (25%) Reason for treatment failure Death Death 0 (0%) 2 (1%) 1 (1%) Withdrawal due to AE Withdrawal due to AE 23 (16%) 10 (7%) 8 (7%) Need to resume CNI Need to resume CNI 5 (3%) 0 (0%) Need to withdraw therapy Need to withdraw therapy 5 (3%) 11 (7%) 11 (9%) Lost to follow-up Lost to follow-up 10 (7%) 12 (8%) 10 (8%) Withdrew consent Withdrew consent 1 (1%) 0 (0%) Treatment Failure, n (%) *Events are mutually exclusive; only the first event counted per patient. *P = NS for MMF/SRL vs. MMF/CNI.

71 MMF/SRLN=148MMF/CNIN=153 Diarrhea 50 (34%) 47 (31%) Peripheral edema 39 (26%) 20 (13%) Hyperlipidemia 35 (24%) 13 (8%) Leukopenia 33 (22%) 29 (19%) Anemia 23 (16%) 18 (12%) Hypertension 23 (16%) 12 (8%) Mouth ulceration 21 (14%) 0 (0%) Hypokalemia 20 (14%) 6 (4%) Upper respiratory tract infection 19 (13%) 16 (10%) Cough 16 (11%) 16 (10%) Serum creatinine increased 13 (9%) 31 (20%) 31 (20%) Urinary tract infections 20 (14%) 30 (20%) Opportunistic infections 16 (11%) 27 (18%) Adverse Events Post-randomization in >10% of Patients, n (%)

72 MMF/SRLN=148MMF/CNIN=153 Mouth ulceration 7 (6%) Proteinuria 3 (2%) Focal segmental glomerulosclerosis glomerulosclerosis 2 (1%) Leukopenia Diarrhea 1 (<1%) 4 (3%) BK virus infection 3 (2%) Blood creatinine increased 1 (<1%) 2 (1%) Alopecia Select Adverse Events Causing Withdrawal, n (%)

73 Why is there improvement in the renal histology with CSA or FK reduction or withdrawal?

74 ACEI and ARB Preferred treatment strategies antihypertensive antiproteinuric antiproliferative

75 ACEI and ARB Trade-offs HCT lower by about 5-15% Increased K + ( meq/l) GFR reduced by 15-20% Fire Drill

76 Study Design Open label, randomized clinical trial to compare the effects of ARB plus other drugs (non-ACE inhibitor) versus CCB plus other drugs (non-ACE inhibitor) on renal function and histology in patients with CAN (who already were on reduced dose calcineurin inhibitor).

77 Interim Report 30 patients (ARB, n=16; CCB (n=14) Only reporting biopsy data Years post-TX: 6.1 Mean serum creatinine: 3.5 mg/dl Mean blood pressure: 127/78 mmHg

78 * p<0.05 vs 1 Bx BIOPSY RESULTS AIIAT-1AT-2 TGF-  TGF  R 1 Creatinin e (mg/dl) ARB (n=16) 1 Bx 2.9±   ±0.13.7± ±0.2 2 Bx0.9 ±0.2* 2.0  0.1* 0.9  0.1* 2.3±0.2* 1.7±0.2 * 2.9 ±0.2* CCB (n=14) 1 Bx 2.5 ±   ± ± ±0.1 2 Bx3.2±0.2* 2.7   ±0.2* 3.2 ±0.1* 3.3 ±0.1

79 8-oxoGhMYHTUNEL Caspase- 3 FIB Creatinine (mg/dl) ARB (n=16) 1 Bx 2.9 ±   ± ± ± Bx0.9 ± 0.2* 2.9  0.1* 0.8  0.1* 0.9 ± 0.1*28 ± 6* 2.9 ± 0.2 CCB (n=14) 1 Bx 2.5 ±   ± ± ± Bx2.7 ±   ± ± ± 0.1 * p<0.05 vs 1 Bx BIOPSY RESULTS

80 Conclusions Within 1 year of treatment, ARB attenuates renal tissue expression of AII, TGF-beta, its receptor and decreases DNA damage as well as apoptosis, and increases DNA repair protein. This therapeutic strategy may prove to be helpful in preventing progression of CAN in a fashion analogous to what has been described with ACE inhibitor and AT1 blockers in patients with diabetic and non-diabetic nephropathy.

81 Conclusions Need same standard for systolic/diastolic blood pressure control as indicated in JNC 7: less than 130/80 mmHg, or lower if evidence of clinical proteinuria Routine use of RAAS blockade drugs Effective anti-proteinuric strategies Careful attention to all CV risk reduction strategies; they also impact on renal function

82 Conclusions Modification of immunosuppression is important in some patients to avoid progressive loss of kidney function. Protecting the kidney protects the heart!


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