Tomorrow is another exciting edition of #NephJC. We will be discussing pentoxifylline in diabetic nephropathy. There is a summary of the article at NephJC.com.
In support of that article and to aid the discussion, Christos Argyropoulos has stepped up to the blogger plate to provide some color on pentoxifylline.
- It is a non-selective phosphodiesterase inhibitor. PDEs are enzymes that inactivate cyclic nucleotides and have been organized in 11 families (Table 1 ) based on sequence, structural and pharmacological considerations. Inhibition of PDE4 by PTX (Figure 1)  increases cAMP & stimulates PKA activity.
- Activation of PKA leads to phosphorylation of the cAMP response element binding protein (CREB) which in turn leads to suppression of the TNF-a[2,3] synthesis at the transcriptional level
- Inhibition of cAMP production by these phosphodiesterases has a broad range of immunomodulatory effects (Table 2)
- The drug also affects red cell deformability and favorably affects microcirculatory blood flow
- “Mainstream” indications: intermittent claudication, vascular dementia, sickling crises, acute alcoholic hepatitis
- Pharmacokinetics: bioavailability (10-30%), elimination (mostly renal as 50-80% of the drug is recovered in the urine), half life (24-48 mins)
|Figure 1: Pentoxifylline (white) complexed with PDE4 (ribbons). Also shown are the Mg2+ and Zn2+ cofactors of PDE4 (spheres)|
|Table 1 Human PDE isozymes|
- PTX alters RBC deformability and improves microcirculation
- Acts as adenosine antagonist (and thus counters vasoconstriction)
- Possible decline in intraglomerular pressure decreasing hyperfiltration and proteinuria
- Anti-cytokine effects on MCP1, TNF, GFs for fibroblasts (CTGF through smad 3/4)
- Antifibrogenic in rat models of CKD (remnant kidney, pyelo, crescentic GN Figure 2)
- In the streptozocin model of diabetic nephropathy prolonged use of PTX was found to reduce renal inflammation (urinary MCP1 and monocytic infiltration in biopsies) and also proteinuria (Figure 3 )
- PTX may even be useful in optimizing renal allograft function after transplantation since it has been experimentally shown to:
- Protects from the acute (and possibly chronic) toxicity of calcineurin inhibitors (reviewed in )
- Decrease cyclosporing-induced renal endothelin release and vasoconstriction 
- It reduces the urinary levels of TNF-alpha, IL-6 and IL-10 [3,9] which are involved in the inflammatory response of renal allograft rejection
|Figure 2 Effect of PTX treatment on accumulation of a-SMA+ myofibroblasts and collagen III in a rat model of crescentic GN|
|Figure 3 Effects of PTX on urinary cytokines and proteinuria in the streptozocin model of diabetic nephropathy|
|Table 3 Animal studies of the antiproteinuric effects of PTX|
Diabetic Kidney Disease
- Compared with placebo, PTX reduced albuminuria, proteinuria and SBP/DBP. The effects on BP were seen in Type 1 but not Type 2 patients (Figure 4)
- Compared with routine care, PTX reduced albuminuria and proteinuria, but did not affect creatinine or BP. Adverse effects were not increased by PTX (Figure 5)
- In head to head comparisons of PTX v.s. ACEi (two studies) and clonidine/methyldopa (1 study):
- There was no significant difference in SCr, albuminuria, proteinuria, or blood pressure between pentoxifylline and the active comparator (captopril or clonidine/methyldopa) for patients with type 1 and type 2 DKD
- CrCl was significantly increased when pentoxifylline was compared to clonidine and methyldopa (MD 10.90 mL/min, 95% CI -1.40 to 20.40) but not captopril (MD 3.26 mL/min, 95% CI -1.05 to 7.59).
|Figure 4 Meta-analysis of studies of PTX v.s. placebo|
|Figure 5 Meta-analysis of studies of PTX v.s. routine care|
- slower eGFR decline (by 4.3 ml/min/1.73m2 95%CI: 3.1-5.5 p less than 0.001)
- decreased proteinuria
- decreased urinary concentration of TNF-alpha
Non-diabetic forms of CKD
|Table 4 Clinical Studies of PTX in non-diabetic kidney disease|
|Table 5 Effects of PTX v.s. placebo on eGFR slope|
|Figure 7 Probability of renal survival in patients treated with PTX+ACEi/ARB v.s. ARB stratified on the basis of baseline proteinuria|
- Control Group: 97% in the absence of rejection episode vs. 59% in patients with rejection, Log-Rank = 13.6 P less than 0.001).
- PTX Group:
- 89.3% without vs.
- 72% with rejection;
- Log-Rank =2.3 (NS)
- Between group comparisons 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)
|Figure 8 Renal Outcomes in kidney transplant patients who received pentoxifylline v.s. placebo|
- Are the effects of PTX on proteinuria distinct from its effects on eGFR?
- What are the predictors of response at the individual patient level?
- How soon should PTX be started in order to achieve its maximal effect?
- Can PTX be used to reduce proteinuria and stabilize eGFR in patients who are not proteinuric at baseline?
- Will PTX have a beneficial effect in patients who are intolerant of ACEis or ARBs?
To answer these questions, a number of clinical projects will have to be designed. In particular, future studies should include a large number of patients with diabetic and non-diabetic kidney disease on maximal RASi therapy for a randomized assessment of PTX in a double blinded, placebo controlled fashion. Studies specific to immunologically mediated renal diseases e.g. SLE or crescentic GNs should be considered, given the existence of promising animal studies. For patients who are intolerant of RASi (e.g. development of hyperkalemia or reduction of eGFR), a large scale replication of the study by Perkins to assess the effects of PTX on eGFR slope before and after therapy should be contemplated. In all these studies, predictors of response should be sought among clinical, laboratory (e.g. proteinuria/albuminuria/baseline eGFR and its slope) and inflammatory biomarkers (e.g. cytokine levels in blood and urine) to obtain a better understanding of the effects of PTX in renal disease.
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