Pentoxifylline in renal disease, a tour through the literature

In wild anticipation of next week’s #NephJC on Pentoxifylline (PTX)  let’s go over some of the known facts about the drug:

• It is a non-selective phosphodiesterase inhibitor.  PDEs are enzymes that inactivate cyclic nucleotides and have been organized in 11 families (Table 1 [1]) based on sequence, structural and pharmacological considerations. Inhibition of PDE4 by PTX (Figure 1) [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[1])
• The drug also affects red cell deformability and favorably affects microcirculatory blood flow
• “Mainstream” indications: intermittent claudication, vascular dementia, sickling crises, acute alcoholic hepatitis

Figure 1: Pentoxifylline (white) complexed with PDE4 (ribbons). Also shown are the Mg2+ and Zn2+ cofactors of PDE4 (spheres)

• Pharmacokinetics: bioavailability (10-30%), elimination (mostly renal as 50-80% of the drug is recovered in the urine), half life (24-48 mins)

Table 2 Effects of PDE inhibition on human inflammatory cells

 Pharmacological considerations would lead one to anticipate that PTX  will exert a favorable effect on diabetic (or any other form) of kidney disease, since: 

1. PTX alters RBC deformability and improves microcirculation
2. Acts as adenosine antagonist (and thus counters vasoconstriction)
3. Possible decline in intraglomerular pressure decreasing hyperfiltration and proteinuria
4. Anti-cytokine effects on MCP1[4], TNF, GFs for fibroblasts (CTGF through smad 3/4) 
5. Antifibrogenic in rat models of CKD (remnant kidney, pyelo, crescentic GN Figure 2[5])
6. 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 [6])
7. PTX may even be useful in optimizing renal allograft function after transplantation since it has been experimentally shown to:
8. Protects from the acute (and possibly chronic) toxicity of calcineurin inhibitors (reviewed in [7])
9. Decrease cyclosporing-induced renal endothelin release and vasoconstriction [8]
10. 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

The non-clinical, experimental data supporting the use of PTX in renal fibrosis involve both diabetic and non-diabetic forms of disease and are summarized in Table 3. In all these studies PTX exhibited a strong anti-proteinuric effect, while inhibiting renal fibrosis and renal cytokine use [10]

What is the current clinical evidence supporting the use of PTX in various forms of renal disease?

Due to the inferred potential of PTX to amelioriate renal inflammation and fibrosis, there have been numerous, small studies in various renal conditions. 

The role of PTX in diabetic nephropathy was recently examined in a Cochrane group meta-analysis[11] of 17 randomized controlled trials of 991 participants with diabetic kidney disease. The methodological quality of these studies was poor: only 4/17 reported the method of randomization, no study reported the method of allocation and only 9/17 were at low risk of bias.  

• 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).

Though somewhat promising, the limitations in the primary data sources led the Cochrane group authors to conclude: “Evidence to support the use of pentoxifylline for DKD was insufficient to develop recommendations for its use in this patient population. Rigorously designed, randomised, multicentre, large scale studies of pentoxifylline for DKD are needed to further assess its therapeutic effects.”

In the PREDIAN[12] , prospective, randomized, open-label study of patients with diabetic kidney disease due to type 2 diabetes and CKD stages 3-4, the use of PTX (1200mg/day) on top of Renin Angiotensin System Inhbitors (RASi) for two years resulted in 

• 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

A small number of small studies with small follow up have been reported in the literature. Though no quantitative evidence synthesis has been undertaken, a qualitative appraisal of these studies (Table 4 [10]) suggests that PTX may reduce proteinuria and possibly stabilize eGFR. Among these studies, the one by Perkins was unique in examining the effects of PTX on the eGFR slope before and after the initiation of PTX (Figure 6 and Table 5). For pentoxifylline-treated participants, the mean estimated GFR decrease during treatment was slower compared with the year before study enrollment (−9.6 ± 11.9 mL/min/1.73 m2/y; mean difference, −8.4 mL/min/1.73 m2/y; 95% confidence interval, −14.8 to −2.1; P = 0.01). In that particular study, PTX had no effect on proteinuria.

Figure 6 Effects of PTX on eGFR slope decline

A single center-retrospective analysis from Taiwan, reported renal outcomes of PTX combined with ACEi/ARB v.s. ACEi/ARB in CKD stages 3b-5. In that study roughly 2/3 of patients received PTX and 21.5% of the study population developed ESRD over a median follow-up of 2.25 years. Though observational, the two groups of patients were well matched with respect to a large number of characteristics (age, gender, BMI, eGFR, BP, hemoglobin, anemia, Ca,P, uric acid, cholesterol, triglyceride and proteinuria) but not diabetes (there were more diabetics in the PTX group: 54.2 v.s. 44.6% p=0.02). Even though PTX did not reduce proteinuria at 1 year of follow-up, pts who received PTX and ACEi/ARB had a ~30% lower (HR 0.694, 95% CI: 0.498-0.968, p=0.031) adjusted (for age, gender, baseline eGFR, diabetes status, hypertension and baseline proteinuria) risk of developing ESRD relative to patients who received ACEi/ARB but no PTX. Interestingly enough, the effects of PTX appear to be limited in the group with baseline proteinuria (UPCR over 1g/g), in unadjusted (Figure 6, p=0.33 v.s. p=0.005) or adjusted analyses (HR: 0.602, 95%CI: 0.413-0.877 p=0.008)

The utility of PTX in clinical renal transplantation was first reported more than 15 years ago [14]. In that study 140 consecutive patients who received a transplant between January 1993 and November 1994 were randomized in a double blinded fashion to receive PTX (starting with the induction of anesthesia) or placebo for at least 6 months after transplant. The immunosuppressive regimen used in that study involved induction with ALG/Steroids/Azathioprine and maintenance with Cyclosporine A either alone or in combination with azathioprine. Acute Rejection, Delayed Graft Function and patient survival rates did not differ in the two patient groups. The use of PTX appeared to be associated with improved renal outcomes in the patients who experienced an acute rejection episode (ACR) (Figure 8)

The actuarial, 1 year survival rates were: 

• 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

More recently[15] the effects of PTX were reported in patients with biopsy proven CAN who had been on standard triple immune suppression (Steroid + calcineurin inhibitor + mycophenolate mofetil). In this single arm study the use of PTX was associated with a short lived (3 month) effect in reducing proteinuria. When individual data were examined 29.4% of patients responded with more than over 50% reduction in proteinuria, while 58.8% (10/17) of patients exhibited stable graft function.

Overall a number of studies have shown the potential utility of PTX in diabetic or non-diabetic kidney disease and renal transplantation. The majority of these studies were limited by number of participants, duration of follow-up and methodology, yet a consistent pattern of reduced proteinuria and possibly stabilization of the loss of renal function emerges. A number of studies have shown that TNF-alpha is implicated in renal fibrosis[16–18] so that the clinical effects of PTX appear a posteriori biologically plausible. Nevertheless a number of questions still remain:

• 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.

References

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