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. 2014 Dec 1;9(12):e113760.
doi: 10.1371/journal.pone.0113760. eCollection 2014.

Creatinine, arsenic metabolism, and renal function in an arsenic-exposed population in Bangladesh

Brandilyn A Peters  1 , Megan N Hall  2 , Xinhua Liu  3 , Y Dana Neugut  1 , J Richard Pilsner  4 , Diane Levy  3 , Vesna Ilievski  1 , Vesna Slavkovich  1 , Tariqul Islam  5 , Pam Factor-Litvak  2 , Joseph H Graziano  1 , Mary V Gamble  1
Affiliations

Creatinine, arsenic metabolism, and renal function in an arsenic-exposed population in Bangladesh

Brandilyn A Peters et al. PLoS One. .

Abstract

Kidney disease is emerging as an arsenic (As)-linked disease outcome, however further evidence of this association is warranted. Our first objective for this paper was to examine the potential renal toxicity of As exposure in Bangladesh. Our second objective relates to examining whether the previously reported positive association between urinary creatinine (uCrn) and As methylation may be explained by renal function. We had hypothesized that these associations relate to supply and demand for s-adenosylmethionine, the methyl donor for both creatine synthesis and As methylation. Alternatively, renal function could influence both As and creatinine excretion, or the As metabolites may influence renal function, which in turn influences uCrn. We conducted a cross-sectional study (N = 478) of adults, composed of a sample recruited in 2001 and a sample recruited in 2003. We assessed renal function using plasma cystatin C, and calculated the estimated glomerular filtration rate (eGFR). Consistent with renal toxicity of As, log-uAs had a marginal inverse association with eGFR in the 2003 sample (b = -5.6, p = 0.07), however this association was not significant in the 2001 sample (b = -1.9, p = 0.24). Adjustment for eGFR did not alter the associations between uCrn and the %uAs metabolites, indicating that GFR does not explain these associations. Increased eGFR was associated with increased odds of having %uInAs >12.2% (2001: OR = 1.01, 95%CI (1.00,1.03); 2003: OR = 1.04, 95%CI (1.01,1.07)). In the 2003 sample only, there was a negative association between eGFR and %uDMA (b = -0.08, p = 0.02). These results may indicate differential effects of renal function on excretion of InAs and DMA. Alternatively, a certain methylation pattern, involving decreased %InAs and increased %DMA, may reduce renal function. Given that these studies were cross-sectional, we cannot distinguish between these two possibilities. Discrepancies between the samples may be due to the higher As exposure, poorer nutrition, and lower As methylation capacity in the 2003 sample.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Arsenic metabolism and creatine synthesis.
(A) Guanadinoacetate methyltransferase (GAMT) and phosphatidyl ethanolamine methyltransferase (PEMT), which catalyze the synthesis of creatine (Cr) and phosphatidylcholine, are the major consumers of S-adenosylmethionine (SAM). Arsenic methyltransferase (AS3MT) uses quantitatively much less SAM. (B) In the first, and rate-limiting, step of Cr biosynthesis, guanadinoacetate (GAA) is formed in the kidney by arginine:glycine amidinotransferase (AGAT). Dietary creatine (e.g. primarily from meat) leads to pre-translational inhibition of AGAT, thereby inhibiting endogenous creatine biosynthesis. GAA is transported to the liver, where it is methylated by GAMT to generate Cr, with SAM as the methyl donor. SAM also serves as the methyl donor for the methylation of trivalent inorganic arsenic (InAsIII) to monomethylarsonic acid (MMAV), and for the methylation of monomethylaronous acid (MMAIII) to dimethylarsinic acid (DMAV). The by-product of these methylation reactions is S-adenosylhomocysteine (SAH). Creatine, whether derived from endogenous biosynthesis or dietary sources, is transported to tissues with high energy requirements such as skeletal muscle, heart, and brain, where it is phosphorylated to phosphoryl-creatine (PCr). PCr is used for the regeneration of ATP during intensive exercise. Creatine and PCr are converted non-enzymatically at a constant rate to creatinine (Crn), which is then excreted in the urine. Image credit: Brandilyn A. Peters.
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