pentoxyfilline in diabetic renal disease and renal transplantation

Focus on Pentoxifylline

Journal Club May 20th 2008

Christos Argyropoulos

Background on PTX

• PDE4 inhibitor that increases cAMP & stimulates PKA activity

• Known inhibitor of TNF-a synthesis at the transcriptional level

• Mainstream indications: intermittent claudication, vascular dementia, sickling crises

• Can it be a “novel” therapy for renal diseases mediated through increased PKA activity and/or inflammatory responses?

PTX in Renal Transplantation

Noel C, Hazzan M, Labalette M, Coppin MC, Jude B, Dessaint JP, Lelievre G.Improvement in the outcome of rejection with pentoxifylline in renaltransplantation: a randomized controlled trial. Transplantation. 1998 Feb 15;65(3):385-9.


• Rationale for carrying out the study:1. The drug modulates the production of cytokines

(including TNF-a)2. Decreases the production of endothelin3. Decreases the production of reactive O2 species

from activated macrophages4. Protects from the acute (and possibly chronic)

toxicity of Calcineurin inhibitors5. Synergistically decreases the production of IL-2,

IFN-gamma and TNF-alpha when used with steroids and/or calcineurin inhibitors in vitro


• Patients: Between January 1993 and November 1994, 140 consecutive patients receiving cadaveric kidney transplantations in a single center were registered in a randomized double-blind study comparing PTX treatment with a placebo.

• F/U: Duration of follow-up was at least 1 year for all patients. Patients received PTX or placebo for 6 months after transplantation


• Intervention: – Prior to grafting, patients in the treatment group

received PTX, 300 mg infused intravenously over 6 hr, starting with the induction of anesthesia.

– PTX was continued intravenously for 48 hr at a dose of 600 mg/day, then substituted by a dose of 800 mg/day (400 mg twice daily) when patients could take po.

– Dose adjustment for renal dysfunction: The drug was increased to 1200 mg orally (400 mg, three times daily) only when serum creatinine was below 3 mg/dl.

• Placebo was given orally with the same time schedule in the control group.


• Induction ISP: ALG + Steroids + AZA (preop+ postop). CSA (12 mg/kg/day ) introduced in day #6 if no DGF

• Maintenance ISP: CSA alone (target level was 300) or AZA+CSA (sensitized patients, regrafted patients). Unclear whether AZA was restarted after any rejection episode

• Anti-rejection regimen: SM pulses (1gm x 3) OR OKT3 for steroid resistant rejections


• Definition of rejection: clinical signs of fever, graft swelling, and tenderness combined with laboratory evidence of an increase in serum creatinine levels after ultrasound exclusion of urinary obstruction. Graft biopsy was used for confirmation when the diagnosis was questionable

• Definition of DGF: Need for HD in the first 7 days post transplant


• Definition of graft failure: Kidney allograft failure was defined as the requirement for dialysis OR death with a functioning allograft.

• Other outcomes: renal function (SCr), proteinuria (mg/d) and hypertension

• Fixed Time assessments: 6 months & 1 yr


• Statistical methods: – Descriptive Statistics: Mean ± SD. – Survival Curves: Kaplan-Meier estimator– Group comparisons:

• Student's t test (unpaired data)• The chi-square test (categorical variables).• Log – rank test (actuarial survival curves)

– Multivariate adjustments: Cox PH model– Statistical analyses were performed at 1 year to compare PTX

and placebo in the overall population (137 patients, near- ITT). – A cohort of 115 of our 137 patients (56 treated with PTX vs. 59

with placebo) was analyzed further, after graft loss and patient death were excluded within the first 3 months


Evaluable patients: 69 patients randomized in the PTX group and 68 in the placebo group (out of the 140).

http://ovidsp.tx.ovid.com/spb/ovidweb.cgi?View+Image=00007890-199802150-00015%7CTT1&S=BCEGFPNGNNDDLNHNNCHLFAMJODPPAA00&WebLinkReturn=Full+Text%3DL%7CS.sh.15.16%7C0%7C00007890-199802150-00015


Early (3 months) events


Outcome of renal function during the first month after transplantation, in all patients, treated or not with

PTX and CsA during the same period

No difference in the rapidity of recovery of renal function


Cumulative incidence of adverse effects in the first 6 months

No difference in the incidence of DGF There was no difference in

the overall survival rates at 1 year between the treated and placebo group (patient survival: 94.3% vs. 94%; graft survival: 80% vs. 78%)

Immunosuppressive treatments and CsA trough levels at 6 months and 1 year. There was no difference in the incidence of hypertension at 1 year between the groups

PTX in Renal TransplantationUnivariate Analysis for Graft Loss: acute graft rejection (relative risk, 6.01; standard error, 1.71;P<0.001)

Within group comparisons (actuarial 1 year survival rate):Control Group: 97% in the absence of rejection episode vs. 59% in patients with rejection, Log-Rank = 13.6 P<0.001). PTX Group: 89.3% without vs. 72% with rejection; Log-Rank =2.3 (NS)

Between group comparisons (actuarial 1 year survival rate)Stratified by ACR (positive or negative) and excluding pts who died or lost their graft in the first 3 months after transplantation

Pts with ACR: Log rank test : 6.66(P=0.01) Pts w/o ACR: Log rank test : 1.8 (NS)


67%

93.5%

97%

59%

89.3%

72%


near – ITT analysis (137 patients)

Actual 95% (CI) (from the Table stats) : 1.01-3.48


Excluding 22 early (< 3 mos) deaths and graft loses (115

pts)

Cox PH Models (no mention of the factors used to adjust these RR models for):

RR ACR: 13.5±2.92,P<0.02

Tx with Placebo: 4.55±2.0, P<0.03.

PTX in Renal TransplantationWhat did the study demonstrate?

Does it contradict/confirm previous studies?

How substantial is the treatment effect?

How safe is the proposed treatment ?

Is the proposed mechanism of action/interpretation of the results a plausible one?

Did the investigators studied signal or noise w.r.t. a key variable/predictor of allograft loss (are the data robust) ?

Are the results applicable to our patient population/local practice patterns?

Is the dosing regimen convenient ?

Are further studies truly needed in this case?

How would one study pentoxifylline in the 21st century?

PTX in Diabetic Kidney Disease

McCormick BB, Sydor A, Akbari A, Fergusson D, Doucette S, Knoll G. The Effect of Pentoxifylline on Proteinuria in Diabetic Kidney Disease: AMeta-analysis. Am J Kidney Dis. 2008 Apr 21.


Rationale for using PTX in DKD:1. PTX alters RBC deformability and improves

microcirculation2. Acts as Adenosine Antagonist (vasoconstrictor)3. Expected to lead to a decline in intraglomerular

pressure → decline in overfiltration and possibly proteinuria

4. Anti-cytokine effects on MCP1, TNF, GFs for fibroblasts (CTGF through smad 3/4)

5. Antifibrogenic in rat models of CKD (remnant kidney, pyelo)


Rationale for carrying out meta-analysis:1. The drug has been “re-discovered” multiple times, since

the initial report in 1982

2. Someone decides to carry out a (small) study, results are published, then the investigator shifts gears, decides to change jobs, ends up on dialysis and the “big” study is never carried out

3. ACEIs and ARBs drastically changed the landscape in the early 90s and studies with “old” antiproteinurics were less likely to be carried out, written up, and published

4. The immunologic basis of DKD has only recently been acknowledged


Primary Outcome for this meta-analysis:1. Change in proteinuria vs RAS blockade

Secondary Outcomes:1. Change in Blood Pressure

2. Changes in GFR


Database sources used for the meta-analysis:

1. MEDLINE (1996 to February 2006)2. EMBASE (1985 to 2005)3. Cochrane Central Register of Controlled

Clinical Trials (to first quarter of 2006)4. Cochrane Database of Systematic

Reviews (to first quarter of 2006)

Journals searched by hand: JASN, AJKD,KI


Keywords used in DB searches:

(pentoxifylline OR Trental)

AND

(diabetes OR diabetic nephropathy OR kidney

failure chronic OR renal insufficiency, chronic OR glomerular filtration rate OR kidney function

tests OR creatinine OR

proteinuria OR albuminuria OR microalbuminuria)

PTX in Diabetic Kidney DiseaseStudy inclusion criteria:1. randomized controlled trial with an intervention arm

that received oral pentoxifylline;2. subjects were adult patients (>18 years) with diabetic

kidney disease defined as albuminuria with greater than 30 mg/d of albumin, or glomerular filtration rate less than 60 mL/min/1.73 m2 (≤1.0 mL/s/1.73m2)

3. Study reported o1 of the following outcomes: I. urinary protein excretion rateII. estimate of glomerular filtration rateIII. serum creatinine level,IV. creatinine clearanceV. or systolic or diastolic blood pressure.

There was no minimum sample size or language restrictionStudy Exclusion Criteria: AKI or Renal Transplant

PTX in Diabetic Kidney DiseaseData gathering and abstraction:1. Two investigators independently

screened the citations identified for their suitability

2. The same investigators read the full text of the publications for their (final) elegibility

3. Disagreements were resolved through arbitration by a third investigator

4. Method quality was assessed by the Jadad scale


Jadad scale:

1.Is the study randomized?

2.Is the study double blinded?

3.Is there a description of withdrawals?

4.Is the randomization adequately described?

5.Is the blindness adequately described?

PTX in Diabetic Kidney DiseaseData gathering and abstraction:1. Two investigators independently screened the

citations identified for their suitability2. The same investigators read the full text of the

publications for their (final) elegibility3. Disagreements were resolved through

arbitration by a third investigator4. Method quality was assessed by the Jadad

scale5. Primary investigators were contacted for

missing data elements (means/SDs)6. For cross-over trials, data from the first period

were utilized

PTX in Diabetic Kidney DiseaseQuantitative Methods:

1. Standard of Care Comparison:

PTX + (ACEI or ARB) vs (ACEI or ARB)

2. Head to Head Comparison:

PTX vs (ACEI or ARB)

3. Prespecified subgroup analysis:

Microalbuminuria vs Overt proteinuria (> 300 mg/d)

PTX in Diabetic Kidney DiseaseQuantitative Methods:• Summary measures were based on a random-effects

model• A pre-post study correlation of 0.5 was assumed to get

an estimate of the (sensitivity analysis also examined values for the correlation coefficient between 0.25 and 0.75)

• Pooled weighted mean differences with 95% confidence intervals (CIs) were calculated.

• Heterogeneity was assessed using the I2 statistic.• Meta-regression analysis also was performed to

investigate possible causes of heterogeneity.• All reported P values are 2 sided, and P less than 0.05

isconsidered statistically significant.


Trial Flow:

637 original studies

44 RCTs

10 studies included in the final analysis


Studies included in the meta-analysis

Small studies (median number

of participants 45)Total # of

participants 476

Median duration of tx: 6 months (range 2-12)9/10: parallel group design

4: standard of care

comparisons2: head to head comparisons

4: drug vs placebo


Quality was low (median Jadad score 3)


Proteinuria


Overt Proteinuria (> 300mg/d)


Microalbuminuria


• Effects on SCr (7 studies): weighted mean difference: 0.004 mg/dL (-0.1 to 0.1, P =0.9)

• Effects of ClCr (4 studies): weighted mean difference 0.6 mL/min (-2.5 to 3.8, P =0.6)

• Effects on SBP (9 trials): weighted mean difference 1.1 mmHg (-0.9 to 3.1, P =0.3)

• Effects on DBP (9 trials): weighted mean difference -0.3 mmHg (-2.3 to 1.7, P =0.7)

• ADRs (5 trials, 358 pts): 7 reported dizziness, 5 GI, 1 headache, 3 (HA + GI)

• Withdrawals: 4 in PTX, 5 in control arms (4 in captopril, 1 placebo)


• Conclusions:1. In short term studies, PTX is associated with

a significant decline in the degree of proteinuria

2. Effect seems to be limited to those with overt proteinuria

3. Quantitatively the effect is similar to ACEI (full dose PTX to 75 mg/d Captopril or 20 mg Lisinopril or 10 mg Ramipril)


• Conclusions:1. It is not known whether the drug will delay

the decline in GFR (long term studies will be needed)

2. It is not known whether additive therapy confers any advantage over combination therapy

3. “Niche” for PTX: patients in whom RAS blockade cannot be used (e.g. hyperK+)


• Interpretation of results in the context of biology/pathophysiology of DKD:

1. DKD is a proinflammatory state

2. Inflammation may aggravate proteinuria (and in turn proteinuria may aggravate inflammation)

3. PTX may block the inflammatory arm directly while ACEIs/ARB may do so both directly and indirectly (by decreasing proteinuria)

4. PTX blocks expression of TGF-beta induced transcription of CTGF and thus may have direct antifibrotic effects


• Limitations of the primary reports:1. Short term studies of low quality2. Open label designs3. Enrolled few patients4. Only 5 studies documented adverse effects (in

particular the bleeding risk of PTX should be assessed more rigorously, given the high prevalence of anticoagulants/anti-PLT in the diabetic population)

5. Dosing regimens were not examined (drug’s dose should be adjusted for ClCr)


• Limitations of the primary reports:6. Submaximal dose of ACEI/ARBs were used

(and some studies did not even report the doses used)

7. Significant study heterogeneity


• Implications for further studies1. Long term, large studies of proteinurics with

DKD

2. PTX should be added to standard of care (ACEI or ARB or ?both)

3. Slope of GFR (or ClCr) should be assessed as well

4. Attention to BP control (because the drug may lower BP)

pentoxyfilline in diabetic renal disease and renal transplantation

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