was increased from 250 to 500 mg/week. After 6 months, 40 percent of patients attained plasma oxalate levels that exceeded the range that would be associated with calcium oxalate super saturation at usual calcium concentration [58]. Elevated plasma oxalate levels also occur in hemodialysis patients treated with oral Vitamin C [48].

The 2006 KDOQI anemia guidelines in CKD conclude insufficient evidence exists to recommend Vitamin C as an adjuvant to Epoetin therapy [35]. The European Best Practice Guidelines suggested that correction of impaired Vitamin C status can reduce hypo responsiveness to EPO or functional iron deficiency, but do not recommend routine use [59]. The guidelines noted that use of high dose Vitamin C requires monitoring but also commented that the risk of oxalate deposition precludes a recommendation for routine use. Also the 2012 KDIGO guidelines recommend not using VITAMIN C, due to lack of sufficient and long term data to address the safety [14].

Further well controlled trials are needed to determine the role of Vitamin C in anemia of CKD. A short trial of oral or IV Vitamin C may be tried in selected patients with marked EPO hypo responsiveness who are closely monitored for toxicity and efficacy, and should be reserved for the patients who are unable to achieve and maintain target hemoglobin levels despite adequate iron stores and on high epoetin therapy (>450 IU/kg per week). The duration of therapy should not be more than 2 to 6 months.

4. Carnitine

Carnitine is required for the transport of long chain fatty acids into mitochondria. Carnitine also converts acyl CoA which accumulates in renal failure and is toxic, into less toxic acyl Carnitine [60]. Carnitine metabolism is reduced as the glomerular filtration rate falls. Its loss through dialysis has been suggested to result in a Carnitine deficient state. L-Carnitine has been used with or without concomitant ESA [61].

Carnitine increases formation of colony forming unitserythroid (CFU-E) colonies in cell cultures of mouse bone marrow [62]. It has also been suggested to increase red cell survival by reducing red cell osmotic fragility. However there is no convincing evidence yet about the importance of this in ESRD.

Small case series suggest intravenous or oral L-Carnitine may increase hemoglobin levels or reduce the EPO requirement in patients with renal failure and on dialysis [61-63].

A 2002 metaanalysis of six randomized trials evaluated the efficacy of IV Carnitine supplementation in lowering the required dose of EPO. The EPO dose was found to be significantly lower among those administered Carnitine, with a beneficial response reported in four of the six studies [63].

Only a few randomized, controlled trials of L-Carnitine exist in patients with CKD. One such trial in hemodialysis patients, found that treatment with intravenous L-Carnitine was associated with a 37% reduction in EPO dose without any effect on hematocrit. Neither hematocrit nor EPO dose changed in the control group. A fall in EPO dose was observed in seven of 13 treated patients with maximal benefit by four months [64].

In an open label randomized trial, 55 adult chronic HD patients at a single hemodialysis center were divided into two groups; a group of 20 patients who received 1500 mg/day oral L-Carnitine and a control group of 35 patients. The mean weekly maintenance dose of erythropoietin was not statistically significantly different in L-Carnitine group (80.16 ± 35.61 units/kg) and the control group (91.9 ± 38.21 units/kg, p = 0.20) [65]. In another randomized control trial involving 14 patients, L Carnitine was not associated with a reduction in EPO dose or change in hematocrit over a six month treatment period [66]. In the post-hoc analysis, there was a nonsignificant trend towards lower EPO dose in patients over the age of 65.

In another study, patients on Hemodialysis received either 5 or 15mg/kg of L Carnitine at each dialysis treatment for 8 months, with IV iron for the first four months with the control group receiving only IV iron. EPO dose did not change over a 4 months period [67]. Mean weekly EPO dose fell by 37% percent among those receiving L-Carnitine.

In two additional randomized trials in which anemia or EPO dose was not the primary endpoint, there was no change in hemoglobin or epogen dose from baseline in patients on L-Carnitine [68,69].

Intravenous L-Carnitine has been well tolerated apart from a small percentage of patients with seizures and has been recommended by some to be used in selected patients with renal failure and EPO resistance, while some have suggested routine use [61]. Treatment with oral Carnitine up to 3 years has been well tolerated [61] with some concern about the accumulation of toxic metabolites of oral L Carnitine in patients with CKD [70,71].

2006 KDOQI guidelines for anemia of CKD concluded that insufficient evidence exists to recommend LCarnitine [72]. The 2012 KDIGI guideline suggest not using L-Carnitine [14].

5. Pentoxifylline

Pentoxifylline is a methyl xanthine derivative with possible anti inflammatory properties [73,74]. Approved for the treatment of peripheral vascular disease, Pentoxifylline has been shown to suppress IL-2, interferon (INF) gamma, TH1 and TH2-derived cytokines [73].

These findings led to the possible application in EPOresistant anemia. The benefits of Pentoxifylline were observed in a small study comprised of 16 patients on HD, PD and failing transplants [75]. The mean hemoglobin increased from 9.5 to 11.7 g/dL. Epo dose was reduced in only one patient while remaining the same in the rest. One patient, previously transfusion-dependent, was able to stop transfusion. In another study 7 anemic patients with CKD were treated with Pentoxifylline 400 mg daily for 6 months with the goal of defining the effects of Petoxifylline as an agent with anti-tumor necrosis factor (TNF) alpha properties. Petoxifylline-treated patients at 6 months had significant improvement in hemoglobin with reduction of TNF-alpha concentration [76]. Thus Pentoxifylline by virtue of counteracting anti-erythropoietic cytokines may allow epogen dose reducetions in the anemia of CKD. This should be followed up with a larger prospective study to confirm these findings before consideration for common practice. The 2012 KDIGO guideline suggests not using Pentoxifylline at this time due to lack of high-quality evidence [14].

6. Statins

Statins are a class of drug use to lower cholesterol by inhibiting HMG-CoA redcutase, which plays a central role in the production of cholesterol in the liver. Statins have some anti-inflammatory and antioxidant properties. In a retrospective study, Sirken et al showed mean hemoglobin rose from 10.6 to 12.5 g/dl in 70 hemodialysis patients, with associated 25% reduction in EPO dose, over a mean of 4.7 months after treatment with statin was started [77]. Roughly half of the patients were started on a statin within one month of starting Hemodialysis, limiting generalizabilty. Another study assessed the efficacy of Statins in patients with type 2 diabetes who were on Hemodialysis. The mean EPO dose was significantly lower in statin group [78]. Another prospective study assessed the effects of statin therapy on EPO hypo responsiveness by assessing the anti-inflammatory effects. 30 patients with baseline cholesterol >220 mg/dl were prescribed 10 mg of Atorvastatin for 12 weeks. EPO hypo responsiveness defined by EPO to hematocrit ratio was significantly reduced along with reductions in Interleukin 6 and TNF-alpha level suggesting that statin therapy may benefit patients with EPO hyporesonsiveness [79]. Further investigation of the effects of Statins as an Epo adjuvant is needed. For now Statins cannot be recommended at this time to be used solely for the treatment of anemia, but remain a central weapon in combating cardiovascular disease, the most common cause of death in patients with CKD [80].

7. Androgens

Before the availability of Epogen, androgens were used routinely to treat anemia in patients with dialysis [81-84]. Androgens may increase endogenous erythropoietin production, sensitivity of erythroid progenitors to the effects of erythropoietin and red blood cell survival. Their role as monotherpay for anemia in CKD patients has declined markedly since epoetin alpha was approved. A possible role of androgens in combination with epoetin therapy in dialysis patient has been evaluated in few small studies with EPO with conflicting results.

One study evaluated 15 patients with ESRD, 8 of whom received intramuscular nandrolone decanoate 1000 mg once weekly in combination with EPO with each dialysis session (the remaining 7 received no androgens). The combination was associated with a greater increase in hematocrit values from 24 to 33 percent as well as greater overall response rate defined as having an increase in hematocrit of 1% during a two week period. The authors concluded that androgen therapy significantly augments exogenous Epo, resulting in a lower dose of intravenous EPO [85].

A second trial enrolled 12 hemodialysis patients, randomly assigned to receive EPO 40 units/kg IV three times weekly with or without nandrolone decanoate (2 mg/kg IM weekly) for 16 weeks. The rate of rise of hematocrit did not differ, and only one of six patients receiving nandrolone reached the HCT target of 30 percent as compared to 3 in the Epo-only group [86].

In another longer open label trial, with low dose EPO therapy [87] 19 chronic HD patients were randomly assigned to receive EPO 1500 units with each HD treatment either alone or in combination with nandrolone decanoate 100 mg intramuscularly each week for 26 weeks. With no serious side effects reported, nandrolone group achieved higher final hematocrit values than Epo-alone group (33.2% vs 28.3%) with higher mean increase in hematocrit (8.2% vs 3.5%).

Another study of 32 hemodialysis patients randomly assigned to receive low dose EPO therapy 1000 units subcutaneously at each HD treatment either alone or in combination with nandrolone decanoate 50 mg intramuscularly twice weekly for six months showed no statistically significant rise in HCT in nandrolone group compared with the control group with significant side effects of gynecomastia, hirsutism, menstrual irregularities and increase in liver enzymes and triglycerides [88].

The data on androgens are conflicting; prompting both the NKF-K/DOQI and European Best Practice Guideline to conclude their role is limited and further complicated by unwanted side effects [35,59]. Cost itself also limits the role of androgens. The 2006 KDOQI guidelines for anemia in CKD stated that androgens should not be used as an adjuvant to epoetin alfa [35]. The 2012 KDIGO guidelines recommend not using androgens.

8. N-Acetylecysteine

N-Acetylecysteine (NAC) is used primarily as a mucolytic, for acetaminophen overdoses, and to prevent contrast induced nephropathy [89,90]. Due to lack of benefit in preventing contrast induced nephropathy in a recent trial [91], NAC is falling out of favor, but still recommended by KDIGO 2012 to prevent contrast induced nephropathy in high risk patient [92].

There is growing interest in exploring NAC as an adjuvant to EPO due to its antioxidant properties in patients with CKD. In one study, 49 patients on HD received NAC 200mg three times daily for the first 3 months of dialysis, and were compared to 276 patients who did not receive NAC. During the 4-month study, when the EPO dose was stable, only NAC group had significant increase in hematocrit, accompanied with decrease levels of 8-isoprostane and oxidized low-density lipoprotein, both markers of oxidative stress [93].

To determine the contribution of injectable iron administered to HD patients in causing oxidative stress and the beneficial effects of NAC in reducing it, a prospective double blind, cross over trial was conducted on 14 adult hemodialysis patients [94]. To assess for oxidative stress, lipid peroxidation marker, melondiaaldehyde was measured along with highly sensitive C-reactive protein. Non-invasive assessment of endothelial dysfunction was assessed by digital plethysmography before and after intravenous therapy. NAC was found to reduce oxidative stress along with endothelial dysfunction. Thus by reducing the oxidative stress, NAC may reduce EPO hypo-

Table 2. Summary of different ESA adjuvants.

responsiveness.

Another small, uncontrolled pilot study enrolled 12 hemodialysis patients treated with 600 mg po BID of NAC showed a 53% reduction in EPO resistance index (weekly EPO dose per Kg/Hematocrit) [95].

These small studies suggest a role for NAC in treating anemia in CKD population, but need larger controlled trial with less confounding factors. Until then, routine use of NAC as an EPO adjuvant cannot be suggested.

9. Summary (Table 2)

The high cost of ESAs and the rising incidence of mor bidity and mortality associated with its use have prompted a search for adjuvants to ESAs to limit cost and potential toxicities in CKD and ESRD-associated anemia. Adequate iron stores are essential for effective erythropoiesis and should be corrected. Use of parenteral, as opposed to oral, iron, particularly in ESRD, can overcome some EPO resistance. Identifying correctable causes of anemia (B12/Folate deficiency, gastrointestinal bleeding) and nonrenal causes of anemia (malignancy, hematologic disorders, infections, inflammation) remains vital, as escalating doses of EPO can lead to morbidity and mortality.

Thus far, no one particular adjuvant has proven to be reliably efficacious in improving anemia, reducing ESA dosages, or reducing ESA hyporesonsiveness. IV iron and ESA remain the backbone of all anemia therapy in ESRD. Nevertheless, this review will serve to generate new hypotheses, and may lead to new innovations in anemia management. We believe that Ascorbic Acid, N-Acetyl Cysteine, and targeting hepcidin represent the most promising ways to combat the erythropoietin hypo response, but due to lack of sufficient high quality evidence, should not be routinely use.

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