1. Journal Club November 2014 By Sourabh Chand ST6

2. What we know Pentoxifylline – Non-selective phosphodiesterase inhibitor Prevents cAMP inactivation and increases PKA activity CREB PO4 -n = TNF-α synthesis suppression – used for >30 years – Intermittent claudication – Vascular Dementia – Sickling crises – Acute Alcoholic hepatitis Dual blockade and bardoxolone unsafe in this group

3. Anti: inflammatory (MCP1), oxidative stress, fibrotic (Smad 3/4)

5. The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis. McCormick BB, Sydor A, Akbari A, Fergusson D, Doucette S, Knoll G. Am J Kidney Dis. 2008 Sep;52(3):454-63.

6. Implications for practice Although pentoxifylline may confer positive effects on kidney function, albuminuria and proteinuria levels, with a low adverse event profile. However the poor methodological quality of included studies, the small number of patients enrolled, and likelihood of publication bias, provided insufficient evidence to support the routine use of pentoxifylline for treating patients with type 1 and type 2 DKD. Cochrane review 2012

8. The PREDIAN study Randomised, prospective, single- centred (3°), open label study – Numbered letter randomisation – Lab measurements blinded – White patients only T2DMs, clinical practice targets: – HbA1c <7%, LDL < 100mg/dl, Bp <130/80 (except CVD then <140/90) Given 600mg extended release PTF 1/12 then bd

9. Criteria Inclusion: – >40yr, ADA T2DM and DN (?biopsied) with diabetic retinopathy, DM>8yrs, CKD 3-4, UAE>30mg/day, 6months. Exclusion: – T1DM, nondiabetic kidney disease, hx of chronic inflam/immuno/tumoral disease, acute inflam/infectious disease within prev 3/12, in-patients, receipt of immunotherapy/suppression, prev PTF use, dual blockade or aldosterone antagonists or direct renin inhibitors, bp≥180/110, breastfeeding, plans of pregnancy, sexually active and not using birth control.

10. Outcomes Primary: – Progression of DKD via change in eGFR after 2yr F/U (measured every 6 months) Secondary: – % pts with eGFR reduction ≥25% – % pts eGFR decline >median decline rate/month – UAE change Tertiary: – Urinary TNF-α (and its relationship with eGFR & UAE change)

11. Methods Pill diary – adherent if 95%) F/u 3-6 months – identical for both – Adherence, other med use, bloods each clinic – 24 hr UAE (and ACR) every 6 months – 8-12hr fast prior to bloods – eGFR MDRD – ELISA for urinary TNF-α Concentrations normalised to urinary creatinine

12. Flow diagram of participants in the study. Navarro-González J F et al. JASN doi:10.1681/ASN.2014010012 ©2014 by American Society of Nephrology

13. CharacteristicControl Group (n=87)Pentoxifylline Group (n=82) Demographic characteristics Age (yr) 69.5±9.570.2±8.9 Men (%) 46 (52.8)45 (54.8) Clinical characteristics Known duration of diabetes (yr) 14.8±3.515.3±3.2 CKD stage 3, n (%) 63 (72.4)53 (64.6) CKD stage 4, n (%) 24 (27.5)29 (35.3) Body mass index (kg/m 2 ) 28.9±2.929.4±3 Systolic BP (mmHg) 141.8±8.4142.2±9.4 Diastolic BP (mmHg) 86.4±7.786.5±8.5 Biochemical variables Hemoglobin A1c (%) 7.2±0.77.3±0.7 Cholesterol (mmol/L) Total 4.5±0.84.3±1.0 LDL 2.4±0.62.3±0.6 HDL 1.1±0.31.0±0.2 Triglycerides (mmol/L) 1.8±0.91.8±0.7 Serum albumin (g/dl) 4.04±0.304.01±0.25 eGFR (ml/min per 1.73 m 2 ) 37.6±11.937.1±12.4 UAE (mg/d) 1000 (600–1800)1100 (689–2190) UAE>1 g/d, n (%) 43 (49.4)49 (59.7) Urinary TNF-α (ng/g) 16 (9.1–22)16 (11–20.1) Medical history, n (%) Hypertension 87 (100)82 (100) Hyperlipidemia 84 (96)78 (95) Coronary heart disease 41 (47)35 (42) Congestive heart disease 18 (20)15 (18) Stroke 3 (3)2 (2) Peripheral vascular disease 23 (26)21 (25) Concomitant medication use, n (%) Insulin 43 (47)40 (48) ACEIs 40 (46)32 (39) ARBs 47 (54)50 (61) Diuretic 70 (80)67 (82) Calcium-channel blockers 52 (59)45 (54) β-Blocker 40 (45)38 (46) α-Blocker 15 (17)17 (21) Central-acting agents 9 (10)4 (8) Statins 80 (92)74 (90) Aspirin 78 (89)71 (86) Baseline characteristics of participants in the trial

14. Sample size calculation Mean eGFR rate decline of 0.45±0.36 ml/min/1.73m 2 /month – Based on 2001 Lewis et al study – Used creatinine clearance not eGFR – Younger (60) – 69% retinopathy – UAE higher 1900 – DM control poorer 8% – Bp higher target 135/85 Powered for 35% difference eGFR change – Total trial size 168, 80% power, 2-tail 5% significance, allowing for a 5% dropout rate.

15. RESULTS

16. Evolution of average systolic and diastolic BP at randomization (basal) and during follow-up in the control and PTF groups without any significant difference between groups. Navarro-González J F et al. JASN doi:10.1681/ASN.2014010012 ©2014 by American Society of Nephrology

17. Evolution of the mean eGFR at randomization (basal) and during follow-up in the control and PTF groups. Navarro-González J F et al. JASN doi:10.1681/ASN.2014010012 ©2014 by American Society of Nephrology

18. Change in eGFR and UAE from baseline to the end of the study. Navarro-González J F et al. JASN doi:10.1681/ASN.2014010012 ©2014 by American Society of Nephrology

19. VariableControl GroupPTF GroupP Value between Groups eGFR (ml/min/1.73 m 2 ) Mean baseline±SD 37.6±11.937.1±12.4 Least-square mean change±SEM (95% CI) per follow-up period 6 mo −1.7±0.1 (−2.1 to −1.4)−1.4±0.1 (−1.7 to −1.0)0.1 12 mo −3.4±0.3 (−4.1 to −2.8)−1.2±0.3 (−1.9 to -0.6)<0.001 18 mo −5.3±0.3 (−6.1 to −4.5)−1.7±0.4 (−2.5 to -0.9)<0.0001 24 mo −6.5±0.4 (−7.3 to −5.6)−2.1±0.4 (−3.0 to -1.2)<0.0001 UAE Median baseline (IQR) (mg/d) 1000 (600–1800)1100 (689–2190) Least-square mean percentage change per follow-up period±SEM (95% CI) 6 mo 1.4±1.1 (−0.8 to 3.8)−10.6±1.2 (−13.0 to -8.2)<0.001 12 mo 4.9±2.8 (−0.7 to 10.6)−13.0±2.9 (−18.8 to −7.2)<0.0001 18 mo 4.9±2.6 (−0.3 to 10.1)−14.8±2.7 (−20.1 to −9.4)<0.0001 24 mo 5.7±2.7 (−0.3 to 11.1)−14.9±2.7 (−20.4 to −9.4)<0.0001 Patients per follow-up period (n) 6 mo 8781 12 mo 8581 18 mo 8479 24 mo 8278 Changes from baseline in eGFR and albuminuria at follow-up visits by study group

20. Percentage of patients with an eGFR reduction greater than the median decline observed in the overall group and >25% with regard to baseline according to study group. Navarro-González J F et al. JASN doi:10.1681/ASN.2014010012 ©2014 by American Society of Nephrology

21. Adverse EventsControl Group (n=87)PTF Group (n=82)P Value Hospitalization episodes 32 (36.7)24 (29.2)0.29 Cardiovascular events Myocardial infarction 2 (2.3)1 (1.2)0.59 Stroke 2 (2.3)1 (1.2)0.59 Heart failure 4 (4.5)3 (3.6)0.75 Revascularization 5 (5.7)2 (2.4)0.28 Syncope 1 (1.1)0 Noncardiovascular events ESRD 3 (5.7)2 (2.4)0.60 AKI 4 (4.5)5 (6.0)0.31 Digestive symptoms 9 (10.3)18 (21.9)0.03 Hemorrhoid bleed 2 (2.3)1 (1.2)0.59 Pneumonia 1 (1.1)2 (2.4)0.52 Eye disorders 3 (5.7)3 (3.6)0.94 Malignant neoplasms 1 (1.1)0 Summary of adverse events in study participants Well tolerated (1 pt PTF withdrew)

22. Summary of Results – PTF vs control Primary: – Progression of DKD via change in eGFR after 2yr F/U (measured every 6 months) – eGFR reduced by 2.1±0.4ml/min vs 6.5±0.4ml/min (p<0.001) Secondary: – % pts with eGFR reduction ≥25% (3.8% vs 26.8%, p<0.001) – % pts eGFR decline >median decline rate/month @ 0.16ml/min (33.3% vs 68.2%, p<0.001) – UAE change: 1100 to 973 (IQR 574-1780) vs 1000 to 1117 (IQR 584-1762), p<0.001 -14.9% vs +5.7% - mean difference 20.6% (95%CI 12.9-28.3%), p<0.001 Tertiary: – Urinary TNF-α (and its relationship with eGFR & UAE change) Median urinary concentration 16ng/g (IQR 10-20.1) overall – Positively correlated with UAE combined: r=0.38, p<0.01 (reduction in PTF +ve UAE; -ve eGFR; r=0.6) – 16 to 14.3 (PTF (p<0.01) and no significant change in control) (-11.5% to +5.1%, p<0.01)

23. Strengths Strengths: – Well characterised and matched – Validation of measurements – Randomised, prospective – eGFR endpoint than previous study focus on proteinuria – Lab measurements blinded – High risk group for progression and the inclusion of those with diabetic retinopathy – Homogenous disease group – Investigator led (none commercial interest) – Treatment relatively cheap and well tolerated, easy to administer – Maximised current best practice medication, standard clinic f/u

24. Concerns Open label Lack of placebo group Relatively hypertensive for this high risk group Non-replication Were these patient’s biopsied to prove DN? Outcomes: CV and ESRF outcome, short f/u, lack of mechanism/identification of those that benefit – just urinary TNF-α Why limited effect at earlier time-points? Could T1DMs be also investigated? How was the dose decided? No smoking history Power calculation Generalisability to other ethnic groups Is the benefit sustained? What happens if drug is stopped? What about those with early CKD stages or microalbuminuria (rather than nephrotic range)

25. Future Avoidance of many single centre studies and subsequent meta-analysis – For RCT, double-blinded, placebo controlled, prospective, multi-centred study – Investigating different ethnic groups – Further profile of the mechanistic parameters – inc protocol biopsies RCTs in other renal diseases and PTX (esp proteinuric/fibrotic) PREDIAN study offers a very promising step-forward in this difficult, high risk population with T2DM with PTX use