Journal Club November 2014By

Sourabh Chand ST6

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

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

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.

Implications for practice Although pentoxifylline may confer positive effects on kidneyfunction, albuminuria and proteinuria levels, with a low adverseevent profile. However the poor methodological quality of includedstudies, the small number of patients enrolled, and likelihoodof publication bias, provided insufficient evidence to supportthe routine use of pentoxifylline for treating patients with type 1and type 2 DKD.

Cochrane review 2012

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

Criteria

• Inclusion:– >40yr, ADA T2DM and DN (?biopsied) with diabetic retinopathy,

DM>8yrs, CKD 3-4, UAE>30mg/day, <15% creatinine variability compared with 4-8wks prior to enrolement, ACE/ARB use at maximum dose >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.

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)

Methods

• Pill diary– adherent if <10% missed over 6/12 (both >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

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

Characteristic Control Group (n=87) Pentoxifylline Group (n=82) Demographic characteristics Age (yr) 69.5±9.5 70.2±8.9 Men (%) 46 (52.8) 45 (54.8)Clinical characteristics Known duration of diabetes (yr) 14.8±3.5 15.3±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/m2) 28.9±2.9 29.4±3 Systolic BP (mmHg) 141.8±8.4 142.2±9.4 Diastolic BP (mmHg) 86.4±7.7 86.5±8.5

Biochemical variables Hemoglobin A1c (%) 7.2±0.7 7.3±0.7 Cholesterol (mmol/L)  Total 4.5±0.8 4.3±1.0  LDL 2.4±0.6 2.3±0.6  HDL 1.1±0.3 1.0±0.2 Triglycerides (mmol/L) 1.8±0.9 1.8±0.7 Serum albumin (g/dl) 4.04±0.30 4.01±0.25 eGFR (ml/min per 1.73 m2) 37.6±11.9 37.1±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

Sample size calculation

• Mean eGFR rate decline of 0.45±0.36 ml/min/1.73m2/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.

RESULTS

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

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

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

Variable Control Group PTF Group P Value between Groups

eGFR (ml/min/1.73 m2)

Mean baseline±SD 37.6±11.9 37.1±12.4Least-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 mo1.4±1.1 (−0.8 to 3.8) −10.6±1.2 (−13.0 to -8.2) <0.001

  12 mo4.9±2.8 (−0.7 to 10.6) −13.0±2.9 (−18.8 to −7.2) <0.0001

  18 mo4.9±2.6 (−0.3 to 10.1) −14.8±2.7 (−20.1 to −9.4) <0.0001

  24 mo5.7±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 87 81 12 mo 85 81 18 mo 84 79 24 mo 82 78

Changes from baseline in eGFR and albuminuria at follow-up visits by study group

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

Adverse Events Control Group (n=87) PTF Group (n=82) P Value

Hospitalization episodes 32 (36.7) 24 (29.2) 0.29Cardiovascular 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)

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)

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

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)

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