letter to the editor

aluminum (Al) absorption in patients taking Al-containing phosphate binders but did not elaborate on this point. We showed that ingestion of a low dose of citrate contained in a well-known effervescent calcium supplement taken by normal volunteers as well as subjects with stable chronic renal failure resulted in an increase in the excretion of urinary Al in normal individuals and an increase in both serum and urine Al in those with CKD.2 The experiments showing this were accompanied by a low dose of Al hydroxide supplementation. The point of the research, however, was to alert medical practitioners that, even without Al supplementation, patients with CKD 3b, 4, and 5 may experience an increase in serum and urine Al if receiving compounds containing citrate. This is because all foodstuffs in a powdery form contain Al to prevent them from congealing, as AL has hydrophobic properties. For this reason we believe that all citratecontaining preparations are totally contraindicated because of the Al contained in, e.g., flour, custard powder, salt, sugar, etc. Although the bicarbonate powder may occasionally be unpleasant to take, it is safe and inexpensive, and the unpleasant taste can be disguised. 1.

2.

Łoniewski I, Wesson DE. Bicarbonate therapy for prevention of chronic kidney disease progression. Kidney Int 2014; 85: 529–535. Nestel AW, Meyers AM, Paiker J et al. Effect of calcium supplement preparation containing small amounts of citrate on the absorption of aluminium in normal subjects and in renal failure patients. Nephron 1994; 68: 197–201.

Anthony M. Meyers1,2

diet alone4,5 or in combination with sodium bicarbonate6 might be an effective alternative approach. Ongoing clinical studies of sodium bicarbonate therapy in CKD patients should also bring more light on the efficacy and tolerability of alkali therapy.7 1. 2.

3.

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Meyers A. Regarding mini-review on bicarbonate therapy for prevention of chronic kidney disease progression. Kidney Int 2015; 87: 1268–1269. Breitkreutz J, Gan TG, Schneider B et al. Enteric-coated solid dosage forms containing sodium bicarbonate as a drug substance: an exception from the rule? J Pharm Pharmacol 2007; 59: 59–65. Rossier A, Bullani R, Burnier M et al. Bicarbonate de sodium pour ralentir la progression de la maladie rénale chronique. Rev Med Suisse 2011; 7: 478–482. Goraya N, Simoni J, Jo CH et al. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol 2013; 8: 371–381. Goraya N, Simoni J, Jo CH et al. Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate. Kidney Int 2014; 86: 1031–1038. Loniewski I. Combining a fruit and vegetable diet with sodium bicarbonate supplementation seems the best dietary option for chronic kidney disease patients. Kidney Int. 2012; 82: 937. Dobre M, Rahman M, Hostetter TH. Current status of bicarbonate in CKD. J Am Soc Nephrol 2014; 26: 515–523.

Igor Łoniewski1 and Donald E. Wesson2,3 1

Sanum Polska Sp. z o.o. ul. Kurza Stopka 5/c, Szczecin, Poland; 2Departments of Internal Medicine, Baylor Scott and White Health, Temple, Texas, USA and 3 Texas A&M Health Sciences Center College of Medicine, Temple, Texas, USA Correspondence: Donald E. Wesson, Texas A&M Health Sciences Center College of Medicine, Baylor Scott and White Health, 2401 South 31st Street, Temple 76508, Texas, USA. E-mail: [email protected] Kidney International (2015) 87, 1261; doi:10.1038/ki.2015.84

1

Dialysis Unit, WITS Donald Gordon Medical Centre, Johannesburg, South Africa and 2Division of Nephrology, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa Correspondence: Anthony M. Meyers, Division of Nephrology, Department of Medicine, University of the Witwatersrand, 402 Waterfall Hills, Private Bag x 5, SunnighHill, Johannesburg 2157, South Africa. E-mail: [email protected]

Intravenous iron dose and mortality in hemodialysis patients

Kidney International (2015) 87, 1260–1261; doi:10.1038/ki.2015.81

The Authors Reply: We thank Professor Meyers for his welcomed comment that citrate intake is responsible for increase in blood and urine aluminum concentration and therefore should be avoided in chronic treatment of metabolic acidosis.1 We agree and suggest that sodium bicarbonate is preferable to sodium citrate as alkali therapy. Galenic forms of sodium bicarbonate should be palatable, easy to swallow, and have pharmaceutical purity and quality. Interestingly, the galenic form of sodium bicarbonate is available as an enteric capsule, which dissolves in intestines.2,3 As such, bicarbonate anions are directly absorbed into the blood. Although we are not aware of clinical studies testing this in CKD patients, it seems that this strategy for sodium bicarbonate administration should yield good clinical efficacy and few if any side effects (e.g., carbon dioxide will not be produced in the stomach). In addition, alkali therapy with fruit and vegetable Kidney International (2015) 87, 1258–1264

To the Editor: There is an important misunderstanding evident in the commentary by Weiss and Kronenberg1 addressing our article2 describing an association between high-dose intravenous iron and mortality in hemodialysis patients. The editorialists state that ‘patients receiving higher dosages of iron also received higher dosages of erythropoiesisstimulating agent (ESA), pointing to bone marrow hyporesponsiveness. It is therefore also conceivable that higher ESA rather than increased iron dosages contribute to mortality in such subjects …’.1 As shown in Table 2 of the manuscript, however, even after adjustment for ESA dose and hemoglobin concentration, average monthly intravenous iron doses ⩾ 400 mg/month were associated with significantly increased mortality compared with the most common doses of 100–199 mg/month (hazard ratio (HR) 1.16; 95% confidence interval (CI) 1.0–1.28) and intravenous iron doses ⩾ 300 mg/ month were associated with significantly increased mortality compared with doses o300 mg/month (HR 1.10; 95% CI 1.03–1.17).2 It is therefore incorrect to ascribe to concomitant ESA administration the observed mortality 1261

letter to the editor

risk associated with intravenous iron prescription. Also, the iron-associated mortality hazard ratios remained of similar magnitude and significance following further adjustment for transferrin saturation and serum ferritin concentration—it does not appear that iron dose was merely a reflection of inflammation as a proximate factor related to mortality. We reiterate our contention that well-powered clinical trials to evaluate the safety of different intravenous iron dosing strategies are urgently needed; we are pleased that the editorialists agreed on this point. 1. 2.

Weiss G, Kronenberg F. Intravenous iron administration: new observations and time for the next steps. Kidney Int 2015; 87: 10–11. Bailie GR, Larkina M, Goodkin DA et al. Data from the Dialysis Outcomes and Practice Patterns Study valídate an association between high intravenous iron doses and mortality. Kidney Int 2015; 87: 162–168.

trials. As outlined in Figure 1 of our commentary,2 these trials will be nevertheless complicated as they have to take into account the most important clinical conditions and treatment options. 1.

Goodkin DA, Bailie GR. Intravenous iron dose and mortality in hemodialysis patients. Kidney Int 2015; 87: 1269–1270. 2. Weiss G, Kronenberg F. Intravenous iron administration: new observations and time for the next steps. Kidney Int 2015; 87: 10–12. 3. Bailie GR, Larkina M, Goodkin DA et al. Association between intravenous iron dose and mortality: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Kidney Int 2015; 87: 162–168. 4. Weiss G, Meusburger E, Radacher G et al. Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin. Kidney Int 2003; 64: 572–578.

Günter Weiss1 and Florian Kronenberg2 1

Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA and Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA Correspondence: David A. Goodkin, 3807 134th Avenue NE, Bellevue, Washington 98005, USA. E-mail: [email protected]

Department of Internal Medicine VI, Medical University of Innsbruck, Innsbruck, Austria and 2Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria Correspondence: Florian Kronenberg, Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Schöpfstr. 41, A-6020 Innsbruck, Austria. E-mail: [email protected]

Kidney International (2015) 87, 1261–1262; doi:10.1038/ki.2015.82

Kidney International (2015) 87, 1262; doi:10.1038/ki.2015.83

David A. Goodkin1 and George R. Bailie2 1 2

The Authors Reply: We appreciate the response by Drs Goodkin and Bailie1 to our recent commentary.2 They are right that the adjustment of the association between IV iron dose and mortality for ESA dose and hemoglobin did not result in a loss of the association, although a weakening was observed. However, Table 1 of their work3 shows that iron and ESA dose are strongly correlated. If high correlation is present, estimates between correlated covariates cannot be distinguished with high certainty. Therefore, a simple adjustment in a statistical model has its limitations, as complex biological interactions cannot really be disentangled. The high correlation between iron and ESA doses suggests a linkage of erythropoetic hyporesponsiveness with mortality. However, this correlation does not confirm a cause–effect relationship. Rather, other mechanisms that impair erythropoiesis, such as inflammation, vitamin deficiencies, blunted activity of erythropoiesis-stimulating hormones, increased hepcidin levels, and not yet identified factors, may underlie this important clinical observation. Although the authors have shown that CRP levels were not different between the groups receiving increasing iron/ESA dosages, it should be mentioned that both iron and ESA exert anti-inflammatory effects and that higher doses of both are associated with reduced circulating inflammatory markers in vivo.4 There is no doubt that the great work by the Dialysis Outcomes and Practice Patterns Study3 and other studies pave the way for long awaited prospective randomized controlled

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Low plasma magnesium and risk of developing chronic kidney disease: results from the PREVEND Study To the Editor: Recently, Tin et al.1 reported that low serum magnesium level was associated with incident chronic kidney disease (CKD). Their large prospective cohort study controlled for many potentially confounding factors, but had the limitation that it lacked measures of albuminuria. This prompted us to examine the association between plasma magnesium and CKD risk in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. This study was specifically designed to investigate the association of albuminuria with risk for cardiovascular and renal disease, and also has data on plasma magnesium levels.2,3 We defined CKD as a creatinine-cystatin C-based eGFR (estimated glomerular filtration rate) o60 ml/min/1.73 m2 and/or albuminuria 430 mg/24 h.4 We studied 5113 participants free of CKD at baseline for a median of 10.3 years. Individuals in the lowest quartile of plasma magnesium levels had a higher risk of developing CKD compared with individuals in the highest quartile, even after multivariable adjustment including 24-h albuminuria (Table 1). Similar associations were observed when we defined CKD as eGFR o60 ml/min/1.73 m2 or as albuminuria 430 mg/24 h. Therefore, our results complement and extend the finding that low serum magnesium level is associated with increased risk of developing CKD.

Kidney International (2015) 87, 1258–1264

Intravenous iron dose and mortality in hemodialysis patients.

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