**11. N-acetylcysteine**

168 Chronic Kidney Disease

early improvement could be detected by the 3rd month, with further increases in the

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

The 2006 K/DOQI guidelines for anemia in CKD stated that there was insufficient evidence

There is no literature available in CKD patients not on dialysis. Before EPO was available, androgens (which may increase endogenous EPO production, sensitivity of erythroid progenitors to the effects of EPO, and red blood cell survival) were used regularly in the treatment of anemia in dialysis patients.**43-46** Their use for anemia in dialysis patients has

Ballal et.al. performed a study in a group of 15 adult male hemodialysis patients.**47** Seven patients were treated with EPO alone at a dose of 2,000 U intravenously (IV) three times a week. An additional group of eight patients was treated with 2,000 U of EPO three times a week and also received 100 mg of nandrolone decanoate intramuscularly (IM) each week. After 12 weeks of therapy, HCT values increased slightly in the group receiving EPO alone, from 25.3+/-0.8 to 27.4+/-1.5. In contrast, EPO in combination with nandrolone decanoate resulted in a greater increase in HCT values, from 24.4+/-1.4 to 32.9 +/-1.8 (p < 0.001). The results showed that the groups receiving low-dose EPO alone had a poor erythropoietic response. In contrast, patients receiving androgen in addition to EPO had a significantly greater increase in HCT values with treatment. These data show that androgen therapy significantly augments the action of exogenous EPO such that lower doses of EPO may be

In a prospective, randomized study by Berns et al. in a chronic hemodialysis population, patients received EPO 40 U/kg intravenously three times weekly either alone (Group 1, n = 6) or with weekly intramuscular injection of 2 mg/kg nandrolone decanoate (Group 2, n = 6) for up to 16 weeks. Baseline HCT, ferritin, N-terminal parathyroid hormone, and aluminum levels were similar. The mean weekly rate of rise in HCT was 0.32+/-0.13% in Group 1 and 0.37+/-0.11% in Group 2, (p = NS). Three of 6 patients in Group 1, but only 1 of 6 patients in Group 2, reached the target HCT of 30% within 16 weeks. Two patients in Group 2 requested that the nandrolone decanoate be stopped prior to reaching target HCT because of unacceptable side effects (acne). **48** Nandrolone decanoate did not enhance the response

In a longer open-label study with low-dose EPO therapy, 19 chronic hemodialysis patients were randomly assigned to receive EPO (1,500 units IV at each HD treatment) either alone

EPO and androgen's combination in hemodialysis patients has been studied:

successive months of treatment in the L-carnitine cohort.

effects include neurological toxicity and uremic breath.

declined markedly since EPO was approved.

sufficient for an adequate hematopoietic response.

rate to this EPO dose and is associated with significant side effects.

to recommend L-carnitine.**<sup>42</sup>**

**10. Androgens** 

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 and 227 not taking NAC, were analyzed for efficacy.

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

Pharmacologic Adjuvants to Reduce Erythropoietin Therapy Dose

Med. 2009;361(21):2019.

Engl J Med. 2006;355(20):2085.

Dis 1999 Sep;34(3):508-13.

Nephron Clin Pract 2005; 11:100.

1996 Nov;50(5):1694-9

Nephrol Dial Transplant 2001 May; 16(5):967-74.

Nephrol. 2006; 26(5):445-54. Epub 2006 Oct 11

in Anemia of Chronic Kidney Disease and End Stage Renal Disease 171

[7] Wolcott DL, Marsh jt, La Rue A, Carr C, Nissenson AR: Recombinant human EPO

[8] Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM,

[9] Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU,

with chronic kidney disease and anemia. N Engl J Med. 2006;355(20):2071. [10] Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D, CHOIR

[11] Fernandez-Rodriguez AM; Guindeo-Casasus MC; Molero-Labarta T; Dominguez-

[12] K/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations for anemia in Chronic Kidney Disease. Am J Kidney Dis 2006; 47(suppl 3):S1 [13] Stoves J; Inglis H; Newstead CG A randomized study of oral vs. intravenous iron

[14] Charytan, C, Ounibi, W, Bailie, GR. Comparison of intravenous iron sucrose to oral iron

[15] Van Wyck DB; Roppolo M; Martinez CO; Mazey RM; McMurray S A randomized,

[16] Agarwal R; Rizkala AR; Bastani B; Kaskas MO; Leehey DJ; Besarab A A randomized

[17] Spinowitz BS, Kausz AT, Baptista J, Noble SD, Sothinathan R, Bernardo MV, Brenner L,

[18] MacDougall IC; Tucker B; Thompson J; Tomson CR; Baker LR; Raine AE A randomized

[19] Wingard RL; Parker RA; Ismail N; Hakim RM Efficacy of oral iron therapy in patients receiving recombinant human EPO. Am J Kidney Dis 1995 Mar; 25(3):433-9. [20] Provenzano R, Schiller B, Rao M, Coyne D, Brenner L, Pereira BJ Ferumoxytol as an

[21] Lipschitz, DA, Bothwell, TH, Seftel, HC, et al. The role of ascorbic acid in the

dialysis-dependent CKD. Kidney Int. 2005 Dec; 68(6):2846-56.

American Society of Nephrology 2008 Aug;19(8):1599-605

the American Society of Nephrology 2009 Feb; 4(2):386-93.

metabolism of storage iron. Br J Haematol 1971; 20:155.

hemodialysis patients. Am J Kidney Dis 13: 478 – 485 , 1989

treatment may improve quality of life and cognitive function in chronic

Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R, TREAT Investigators A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J

Scherhag A, CREATE Investigators Normalization of hemoglobin level in patients

Investigators Correction of anemia with epoetin alfa in chronic kidney disease. N

Cabrera C; Hortal-Casc n L; Perez-Borges P; Vega-Diaz N; Saavedra-Santana P; Palop-Cubillo L Diagnosis of iron deficiency in chronic renal failure Am J Kidney

supplementation in patients with progressive renal insufficiency treated with EPO.

in the treatment of anemic patients with chronic kidney disease not on dialysis.

controlled trial comparing IV iron sucrose to oral iron in anemic patients with non

controlled trial of oral versus intravenous iron in chronic kidney disease Am J

Pereira BJ Ferumoxytol for treating iron deficiency anemia in CKD. Journal of the

controlled study of iron supplementation in patients treated with EPO. Kidney Int

intravenous iron replacement therapy in hemodialysis patients. Clinical Journal of

placebo and the NAC groups. NAC reduced the baseline acute systemic generation of oxidative stress when compared to placebo, which was statistically significant with MDA (12.76 +/- 4.4% vs 9.7 +/- 4.4%) but not with HsCRP. Pre-treatment with NAC reduced the endothelial dysfunction when compared to placebo, but it was not statistically significant.

The author concluded that in those HD patients, NAC reduced the oxidative stress before and after the administration of intravenous iron therapy in addition to the endothelial dysfunction induced by this treatment.**<sup>52</sup>**

Finnigan and Benz reported the results of treating 12 ESRD EPO resistant hemodialysis subjects with oral NAC 600 mg by mouth twice daily for 6 months. In that small pilot study, NAC therapy was associated with a 53% reduction in the EPO Resistance Index (weekly EPO dose/weight in Kg/Hb).**<sup>53</sup>**

These preliminary studies suggest the need for a larger, controlled trial with NAC. Until then, routine use of NAC as an EPO- adjuvant cannot be recommended.
