**7. Pentoxifylline**

Pentoxifylline (PTX) is a methyl xanthine derivative, which is approved for use in peripheral vascular disease and may also have anti-inflammatory effects according to studies. Benbernou et. al. studied pentoxifyline and examined its regulatory effect on T helper (TH1-and TH2) cell-derived cytokines in human whole blood and peripheral blood mononuclear cells stimulated with phytohemagglutinin and phorbol myristate acetate. The results showed that PTX at the appropriate concentrations (5 x 10**(-4)**M ) could induce selective suppression of interleukin (IL) -2 and interferon (INF) -gamma, whereas at high concentrations this drug could act as a suppressive agent of both TH1- and TH2-derived cytokines.**<sup>31</sup>** Bienvenu showed similar results that PTX possesses a much broader spectrum

Pharmacologic Adjuvants to Reduce Erythropoietin Therapy Dose

effect of statins**.36**

inflammation.**<sup>37</sup>**

**9. Carnitine** 

metabolism via ATP formation.

in Anemia of Chronic Kidney Disease and End Stage Renal Disease 167

statin group required EPO dose in excess of an EPO equivalent of 500 units/kg per week, compared to 30.88% in the non-statin group. The two-way analysis of variance showed no interaction between the use of statins and the presence of Type 2 diabetes mellitus on EPO dose. This study demonstrated that hemodialysis patients who were on statins had a significantly lower EPO requirement. This association is possibly due to the pleiotropic

A prospective study tested the effect of statin therapy on ESA hypo- responsiveness, and emphasized its anti-inflammatory benefits in maintenance hemodialysis patients. This study enrolled 30 patients with baseline cholesterol >220 mg/dL. Low-dose atorvastatin (10 mg/day) was prescribed for 12 weeks. They prospectively recorded biochemistry and hematological profiles, ESAs prescription and inflammatory markers at baseline, 4 weeks and 12 weeks. Statistically significant changes were noted after 4 and 12 weeks of statin therapy for cholesterol (272.5 to 184.4 and 196.4 mg/dL, p < 0.05) and ESA hyporesponsiveness, reported as EPO to HCT ratio (EHR) (129.3+/-58.2 to 122.3+/-53.5 and 121.0+/-53.3 EPO U/HCT/week, p < 0.05). Mean values for proinflammatory cytokines included interleukin-6 and TNF-alpha levels decreased by 30.8 and 10.6%, respectively. These data suggest that statin therapy may benefit patients with ESA hypo-responsiveness. This benefit in ESA hypo-responsiveness is associated with the effects of statins on

These preliminary studies may justify future studies to use statins as an EPO dose reducing

L-carnitine is a small molecule (molecular weight: 161.2) that is derived from dietary products, mainly red meat and milk. Endogenous carnitine production takes place in the liver from lysine, methionine, ascorbate, niacin and pyridoxine. L-carnitine is required for the transport of long-chain fatty acids into the mitochondria and is an integral part of energy

L-carnitine has been shown to improve anemia in uremic patients by stabilizing erythrocyte membrane function or erythropoiesis. End-stage renal disease patients are known to have carnitine deficiency.**38** This could be a contributing factor of anemia requiring higher dose of EPO. Thus, it has been used therapeutically in dialysis patients with and without concomitant EPO. Carnitine's role as an adjuvant to EPO in kidney disease is unclear. Most

A 2002 meta-analysis evaluated the efficacy of IV carnitine supplementation in lowering the required dose of EPO using data from six randomized trials. The EPO dose was found to be significantly lower among those administered carnitine, with a beneficial response reported in four of the six studies.**38** Two studies showed improvement in Hb and HCT with PO carnitine but they were published before EPO was available.**39,40** In one study, 24 dialysis anemic patients were divided into two groups, controls (inert placebo), treated patients (Lcarnitine 1.6 g PO daily) for one year. A significant increase in HCT, Hb, red cell count and mean corpuscular Hb concentration was observed. In comparison with the control group, an

adjuvant in patients with inflammation-mediated EPO resistant anemia of CKD.

studies have involved HD patients with IV carnitine administration.

of activity on cytokine production than was initially described, and it appears to be a potential and promising immunotherapeutic agent.**32** These studies led to PTX's possible role in treating EPO resistant anemia. Navarro et. al. conducted a prospective small study of 7 anemic patients with CKD, who were treated with pentoxifylline (400 mg orally daily) for 6 months with the goal of defining the effects of pentoxifylline, as an agent with anti-tumor necrosis factor (TNF)-alpha properties. The results showed Hb significantly increased in the pentoxifylline-treated patients at the 6th month (9.9+/-0.5 g/dL at baseline;10.6+/-0.6 g/dL at the 6th month, respectively, *p* < 0.01), whereas no increase was seen in the control group. Serum EPO levels remained stable in all patients. However, the serum TNF-alpha concentration decreased significantly in patients receiving pentoxifylline. The study suggested that the inhibition of erythropoiesis by cytokines may play a significant role in renal anemia. The administration of agents with anti-cytokine properties, such as pentoxifylline, can improve the hematologic status in this population.**33** Another small study was conducted by Cooper and colleagues on 16 dialysis EPO resistant anemic patients. The patients were treated with oral pentoxifylline 400 mg daily for 4 months. Ex-vivo T cell generation of TNF-alpha and IFN-gamma from the patients was assessed before and 6 to 8 weeks after the therapy. A total of 12 of 16 patients completed the study. Before therapy, mean Hb concentration was 9.5+/-0.9 g/dL. After 4 months, the mean Hb concentration increased to 11.7+/-1.0 g/dL (p = 0.0001). Baseline ex vivo T cell expression of TNF-alpha decreased from 58% +/-11% to 31%+/- 23% (p= 0.0007) after therapy. Likewise, IFN-gamma expression decreased from 31%+/- 10% to 13%+/-10% (p = 0.0002). EPO doses remained unchanged in all but one patient in whom the dose was reduced in response to a higher Hb. One patient who was previously transfusion dependent was able to stop receiving monthly transfusions. Pentoxifylline therapy may significantly improve Hb response in patients with EPO–resistant anemia in renal failure.**<sup>34</sup>**

This small, open-label, uncontrolled study suggests the need for a larger, controlled trial with this agent. Until such a trial is conducted, pentoxifylline is not recommended as an EPO-adjuvant except in the experimental setting.

#### **8. Statins**

Statins (HMG-CoA reductase inhibitors) are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. As mentioned above, cytokines play a role in inhibition of erythropoiesis. Statins have been evaluated as an adjuvant to EPO with the thought that they have anti-oxidant and anti-inflammatory properties. In one retrospective study, 70 HD patients were treated with statins for a period of 4.7 months and were found to have the mean Hb level rise from 10.6 to 12.5 g/dL (*p* < 0.0005) with an associated 25 percent decrease in EPO requirements.**<sup>35</sup>** Another study investigated whether the anti-inflammatory effect of statins improved EPO responsiveness in hemodialysis patients. It examined patients with Type 2 diabetes mellitus, who had been shown to have EPO resistance. One hundred and three patients were stratified into statin and non-statin groups.The outcome of interest was EPO dose. The mean EPO dose (units/kg per week) was significantly lower in the statin group (275.6 ± 273.2, vs. 449.5 ± 555.9, p < 0.05). Twenty percent of patients in the statin group required EPO dose in excess of an EPO equivalent of 500 units/kg per week, compared to 30.88% in the non-statin group. The two-way analysis of variance showed no interaction between the use of statins and the presence of Type 2 diabetes mellitus on EPO dose. This study demonstrated that hemodialysis patients who were on statins had a significantly lower EPO requirement. This association is possibly due to the pleiotropic effect of statins**.36**

A prospective study tested the effect of statin therapy on ESA hypo- responsiveness, and emphasized its anti-inflammatory benefits in maintenance hemodialysis patients. This study enrolled 30 patients with baseline cholesterol >220 mg/dL. Low-dose atorvastatin (10 mg/day) was prescribed for 12 weeks. They prospectively recorded biochemistry and hematological profiles, ESAs prescription and inflammatory markers at baseline, 4 weeks and 12 weeks. Statistically significant changes were noted after 4 and 12 weeks of statin therapy for cholesterol (272.5 to 184.4 and 196.4 mg/dL, p < 0.05) and ESA hyporesponsiveness, reported as EPO to HCT ratio (EHR) (129.3+/-58.2 to 122.3+/-53.5 and 121.0+/-53.3 EPO U/HCT/week, p < 0.05). Mean values for proinflammatory cytokines included interleukin-6 and TNF-alpha levels decreased by 30.8 and 10.6%, respectively. These data suggest that statin therapy may benefit patients with ESA hypo-responsiveness. This benefit in ESA hypo-responsiveness is associated with the effects of statins on inflammation.**<sup>37</sup>**

These preliminary studies may justify future studies to use statins as an EPO dose reducing adjuvant in patients with inflammation-mediated EPO resistant anemia of CKD.
