High urinary homoarginine excretion is associated with low rates of all-cause mortality and graft failure in renal transplant recipients

Frenay, Anne‐Roos S.; Kayaçelebi, Arslan Arinç; Beckmann, Bibiana; Soedamah-Muhtu, Sabita S.; Borst, Martin H. de; Berg, Else van den; Goor, Harry van; Bakker, Stephan J. L.; Tsikas, Dimitrios

doi:10.1007/s00726-015-2038-6

Cited by 34 publications

(18 citation statements)

References 43 publications

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“…Data from studies that we have performed on homoarginine homeostasis in healthy kidney donors and renal transplant recipients suggest that renal contribution to guanidinoacetate synthesis can be even higher if one takes into account that also the arginine required for its synthesis is produced by the kidney [47,48]. For this, it should be realized that the synthesis of homoarginine from arginine is also mediated by the enzyme AGAT, with lysine as a substrate instead of glycine and that, unlike guanidinoacetate—which is metabolized to creatine—homoarginine is currently only known as a metabolic end product, of which urinary excretion approximately equals endogenous production (Figure 2) [47,49]. This has been demonstrated in both rats and pigs, where more than 95% of an orally administered dosage of homoarginine was recovered unmetabolized in the urine [50].…”

Section: Contribution Of the Kidney To Endogenous Synthesis Of Crementioning

confidence: 99%

Creatine is a Conditionally Essential Nutrient in Chronic Kidney Disease: A Hypothesis and Narrative Literature Review

2019

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To accommodate the loss of the plethora of functions of the kidneys, patients with chronic kidney disease require many dietary adjustments, including restrictions on the intake of protein, phosphorus, sodium and potassium. Plant-based foods are increasingly recommended as these foods contain smaller amounts of saturated fatty acids, protein and absorbable phosphorus than meat, generate less acid and are rich in fibers, polyunsaturated fatty acids, magnesium and potassium. Unfortunately, these dietary recommendations cannot prevent the occurrence of many symptoms, which typically include fatigue, impaired cognition, myalgia, muscle weakness, and muscle wasting. One threat coming with the recommendation of low-protein diets in patients with non-dialysis-dependent chronic kidney disease (CKD) and with high-protein diets in patients with dialysis-dependent CKD, particularly with current recommendations towards proteins coming from plant-based sources, is that of creatine deficiency. Creatine is an essential contributor in cellular energy homeostasis, yet on a daily basis 1.6–1.7% of the total creatine pool is degraded. As the average omnivorous diet cannot fully compensate for these losses, the endogenous synthesis of creatine is required for continuous replenishment. Endogenous creatine synthesis involves two enzymatic steps, of which the first step is a metabolic function of the kidney facilitated by the enzyme arginine:glycine amidinotransferase (AGAT). Recent findings strongly suggest that the capacity of renal AGAT, and thus endogenous creatine production, progressively decreases with the increasing degree of CKD, to become absent or virtually absent in dialysis patients. We hypothesize that with increasing degree of CKD, creatine coming from meat and dairy in food increasingly becomes an essential nutrient. This phenomenon will likely be present in patients with CKD stages 3, 4 and 5, but will likely be most pronouncedly present in patients with dialysis-dependent CKD, because of the combination of lowest endogenous production of creatine and unopposed losses of creatine into the dialysate. It is likely that these increased demands for dietary creatine are not sufficiently met. The result of which, may be a creatine deficiency with important contributions to the sarcopenia, fatigue, impaired quality of life, impaired cognition, and premature mortality seen in CKD.

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Section: Contribution Of the Kidney To Endogenous Synthesis Of Crementioning

confidence: 99%

Creatine is a Conditionally Essential Nutrient in Chronic Kidney Disease: A Hypothesis and Narrative Literature Review

2019

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“…Elevated circulating ADMA concentrations are associated with hypertension (Achan et al 2003 ). ADMA and SDMA are considered cardiovascular risk factors and have emerged as predictors of cardiovascular events and death in a range of pathologies, including kidney disease (Busch et al 2006 ; Tain and Hsu 2017 ) and kidney transplantation (Frenay et al 2015a , b ; Said et al 2019a , b ).…”

Section: Introductionmentioning

confidence: 99%

Whole-body arginine dimethylation is associated with all-cause mortality in adult renal transplant recipients

et al. 2021

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Arginine residues in proteins can be singly or doubly methylated post-translationally. Proteolysis of arginine-methylated proteins provides monomethyl arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). ADMA and SDMA are considered cardiovascular risk factors, with the underlying mechanisms being not yet fully understood. SDMA lacks appreciable metabolism and is almost completely eliminated by the kidney, whereas ADMA is extensively metabolized to dimethylamine (DMA), with a minor ADMA fraction of about 10% being excreted unchanged in the urine. Urinary DMA and ADMA are useful measures of whole-body asymmetric arginine-dimethylation, while urinary SDMA serves as a whole-body measure of symmetric arginine-dimethylation. In renal transplant recipients (RTR), we previously found that higher plasma ADMA concentrations and lower urinary ADMA and SDMA concentrations were associated with a higher risk of all-cause mortality. Yet, in this RTR collective, no data were available for urinary DMA. For the present study, we additionally measured the excretion rate of DMA in 24-h collected urine samples of the RTR and of healthy kidney donors in the cohort, with the aim to quantitate whole-body asymmetric (ADMA, DMA) and symmetric (SDMA) arginine-dimethylation. We found that lower DMA excretion rates were associated with higher all-cause mortality, yet not with cardiovascular mortality. In the healthy donors, kidney donation was associated with considerable decreases in ADMA (by − 39%, P < 0.0001) and SDMA (by − 21%, P < 0.0001) excretion rates, yet there was no significant change in DMA (by − 9%, P = 0.226) excretion rate. Our results suggest that protein-arginine dimethylation is altered in RTR compared to healthy kidney donors and that it is pronouncedly shifted from symmetric to asymmetric arginine-dimethylation, with whole-body protein-arginine dimethylation being almost unaffected.

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“…In contrast to ADMA, urinary concentrations of l -homoarginine in humans are low and almost no renal elimination has been measured (Frenay et al 2015 ) possibly due to efficient reabsorption. This suggests that several transport proteins in the luminal and basolateral membrane domain of proximal tubule cells are necessary for the renal handling of this arginine derivative.…”

Section: Discussionmentioning

confidence: 99%

Vectorial transport of the arginine derivatives asymmetric dimethylarginine (ADMA) and l-homoarginine by OATP4C1 and P-glycoprotein studied in double-transfected MDCK cells

et al. 2020

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Elevated plasma concentrations of the uremic toxin asymmetric dimethylarginine (ADMA) and low plasma concentrations of l-homoarginine are independently associated with cardiovascular events and mortality. Key enzymes involved in the homeostasis of both arginine derivatives are expressed in proximal tubule cells of the kidney. To get access to these enzymes, transport proteins are important. One of the transporters mediating the transport of ADMA and l-homoarginine is the solute carrier superfamily (SLC) member OATP4C1, located in the basolateral membrane of proximal tubule cells. To gain insights into the role of export pumps in the transport of both substances, we established a double-transfected MDCK cell line expressing OATP4C1 and the export pump P-glycoprotein (P-gp). Using MDCK cell monolayers, we demonstrated in time-dependent and concentration-dependent vectorial transport experiments that ADMA and l-homoarginine are transported from the basolateral to the apical compartment of MDCK-OATP4C1-P-gp cells with significantly higher transport rates compared to single-transfected MDCK-OATP4C1, MDCK-P-gp and MDCK-VC (control) cells (e.g. transport ratio MDCK-OATP4C1-P-gp/MDCK-VC: for 50 µM ADMA = 2.0-fold, for 50 µM l-homoarginine = 3.4-fold). These results indicate that both OATP4C1 and P-gp transport the arginine derivatives ADMA and l-homoarginine and are, therefore, important for the homoeostasis of both substances.

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High urinary homoarginine excretion is associated with low rates of all-cause mortality and graft failure in renal transplant recipients

Cited by 34 publications

References 43 publications

Creatine is a Conditionally Essential Nutrient in Chronic Kidney Disease: A Hypothesis and Narrative Literature Review

Creatine is a Conditionally Essential Nutrient in Chronic Kidney Disease: A Hypothesis and Narrative Literature Review

Whole-body arginine dimethylation is associated with all-cause mortality in adult renal transplant recipients

Vectorial transport of the arginine derivatives asymmetric dimethylarginine (ADMA) and l-homoarginine by OATP4C1 and P-glycoprotein studied in double-transfected MDCK cells

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