**9. Carnitine**

166 Chronic Kidney Disease

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

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

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

renal failure.**<sup>34</sup>**

**8. Statins** 

EPO-adjuvant except in the experimental setting.

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 metabolism via ATP formation.

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 studies have involved HD patients with IV carnitine administration.

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

Pharmacologic Adjuvants to Reduce Erythropoietin Therapy Dose

common.

**11. N-acetylcysteine** 

and 227 not taking NAC, were analyzed for efficacy.

in Anemia of Chronic Kidney Disease and End Stage Renal Disease 169

or with nandrolone decanoate (100 mg intramuscularly weekly) for 26 weeks.**49** The mean increase in HCT and the final achieved HCT were greater in the nandrolone decanoate treated group (8.2 and 33.2 percent, respectively) than in the group treated with EPO alone

Thirty two hemodialysis patients were randomly assigned to receive low dose EPO therapy (1,000 units SC at each HD treatment) either alone or with nandrolone decanoate 50 mg intramuscularly twice weekly for six months.**50** The increase in Hb in the nandrolone decanoate treated group (from 7.5 to 10.4 g/dL) was not statistically different from the control group (7.3 to 10.0 g/dL). Side effects, including gynecomastia, hirsutism, menstrual irregularity, and increases in liver enzymes and triglyceride levels, were

The limiting factor in these studies was small size and relatively short follow ups, and none attempted to maintain currently recommended Hb levels. The 2006 K DOQI guidelines for

N–acetylcysteine (NAC) is a drug and nutritional supplement used primarily as a mucolytic agent and also in the management of acetaminophen overdose. To explore the efficacy of oral NAC supplementation for anemia and oxidative stress in hemodialysis patients, Chien et al studied 325 dialysis patients. In this study, 49 pateints received NAC 200 mg orally three times a day during the first 3 months of dialysis, while the other 276 patients not receiving NAC were observed. During the 4-month study, 11 patients receiving NAC withdrew but had no severe adverse effects, while 49 patients not receiving NAC had negative confounding events. Thus only the data of the remaining patients, 38 taking NAC

When the EPO dosage was stable, only the NAC group had a significant increase in HCT, accompanied with a decrease in plasma levels of 8-isoprostane and oxidized low-density lipoprotein. Analyzed as a nested case-control study, NAC supplementation was also found to be a significant predictor of positive outcomes in uremic anemia. 51 To determine the contribution of injectable iron administered to hemodialysis patients in causing oxidative stress and the beneficial effect of NAC in reducing it, Swarnalatha et al conducted a prospective, double blinded, controlled, cross over trial on 14 adult hemodialysis patients who were randomized into two groups; one group received NAC in a dose of 600 mgs by mouth twice daily for 10 days prior to intravenous iron therapy and the other group received placebo. Both groups received intravenous iron therapy, 100 mg of iron sucrose in 100 mL of normal saline given over a period of one hour. Blood samples for the markers of oxidative stress were taken before and after the iron therapy. After a week of wash-out period for the effect of NAC, subjects crossed over to the opposite regimen. They measured the lipid peroxidation marker, malondiaaldehyde (MDA), to evaluate the oxidative stress and total anti-oxidant capacity (TAC) for the antioxidant level in addition to the highly sensitive C-reactive protein (HsCRP). Non-invasive assessment of endothelial dysfunction was measured by digital plethysmography before and after intravenous iron therapy. There was an increase of MDA (21.97 + 3.65% vs 7.06 + 3.65%) and highly sensitive C-reactive protein (HsCRP) (11.19 + 24.63% vs 13.19 + 7.7%) after iron administration both in the

(3.5 percent and 28.3 percent, respectively). No serious side effects were reported.

anemia in CKD stated that androgens should not be used as an adjuvant to EPO.

early improvement could be detected by the 3rd month, with further increases in the successive months of treatment in the L-carnitine cohort.

There is some evidence in the literature suggesting that accumulation of metabolites (trimethyleamine and trimethylamines-N-oxide)of oral carnitine, may have potential toxicity**41**. Marcus et.al. conducted a study using oral carnitine and showed that a small dose of L-carnitine is sufficient to increase the blood concentration of carnitine.**41** The concern remains about the accumulation of trimethylamines-N-oxide and its potential toxicologic effects include neurological toxicity and uremic breath.

The 2006 K/DOQI guidelines for anemia in CKD stated that there was insufficient evidence to recommend L-carnitine.**<sup>42</sup>**
