Ergothioneine Depletion in Peritoneal Dialysis

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Abstract

Key Points

• Hemodialysis has been shown to greatly deplete ergothioneine, a diet-derived antioxidant.

• Peritoneal dialysis, which provides lower clearance of solutes, also depletes ergothioneine but to a lesser extent than hemodialysis.

• Whether ergothioneine repletion benefits people receiving dialysis remains to be tested.

Background

Dialysis may deplete the body of valuable solutes. We previously found that the diet-derived antioxidant ergothioneine was markedly depleted in patients on hemodialysis. Standard peritoneal dialysis (PD) prescriptions provide lower clearance of small molecules than standard hemodialysis prescriptions. We, therefore, tested whether ergothioneine would be depleted in patients on PD but to a lesser degree than in patients on hemodialysis.

Methods

Blood levels of ergothioneine were compared in 16 patients on PD, 16 patients on hemodialysis, and 15 controls with normal kidney function. Levels were measured using liquid chromatography-mass spectrometry in plasma and also in erythrocytes in which ergothioneine is normally highly concentrated. Ergothioneine clearances by PD and hemodialysis were also compared.

Results

Erythrocyte ergothioneine levels were much lower in both patients on PD and patients on hemodialysis than controls. The erythrocyte levels in patients on PD averaged 34% of those of controls, whereas levels in patients on hemodialysis averaged only 10% of those of controls. Plasma ergothioneine levels in patients on dialysis were also lower than controls. The time-averaged clearance of ergothioneine was lower with PD than with hemodialysis, so that a standard PD regimen would remove less ergothioneine daily than a standard hemodialysis regimen at a given plasma level.

Conclusions

The antioxidant ergothioneine is depleted in patients on PD but to a lesser extent than in patients on hemodialysis. Benefits of ergothioneine repletion in patients on dialysis remain to be assessed.

Introduction

Dialysis removes solutes indiscriminately. By contrast, the kidneys can reabsorb solutes in the tubules after they are filtered in the glomerulus. Dialysis lacks this vital function and may, therefore, deplete the body of valuable solutes. Solutes which have been recognized as potentially depleted by both peritoneal dialysis (PD) and hemodialysis include carnitine, amino acids, and vitamins.^1,2 Standard PD prescriptions provide lower clearance of small molecules than standard hemodialysis prescriptions.^3–5 Patients receiving PD may, therefore, be less subject to solute depletion than those receiving hemodialysis. Indeed, previous studies have shown that patients on PD have higher levels of carnitine, vitamins B6 and B12, and folate than patients on hemodialysis.^2,6

We previously found that the antioxidant ergothioneine was markedly depleted in patients receiving standard thrice-weekly hemodialysis compared with control participants with normal kidney function.⁷ Ergothioneine, with a mass of 229 Da, is produced only by fungi and bacteria; humans thus obtain it exclusively from the diet.⁸ Extensive in vitro and in vivo data suggest that ergothioneine reduces oxidative and inflammatory injuries.⁹ Ergothioneine deficiency has been increasingly associated with neurologic disorders, and recent trials of ergothioneine supplementation in participants without kidney disease have demonstrated improvements in sleep and cognition.^8,10–13 Perhaps the strongest support for ergothioneine's value is the presence of a highly specific membrane transporter SLC22A4 that avidly takes up ergothioneine at high concentrations into various tissues.¹⁴ Indeed, SLC22A4's affinity for ergothioneine is several-fold higher than other tested compounds.¹⁴ SLC22A4 is abundantly expressed in the small intestine and absorbs ergothioneine from the diet. In addition, renal tubular reabsorption of ergothioneine through SLC22A4 prevents the loss of filtered ergothioneine in the urine. However, ergothioneine is efficiently cleared by hemodialysis so that at the average plasma levels observed in people with normal kidney function, the amount removed by hemodialysis would exceed the average amount obtained from the diet.^15,16 The result is ergothioneine depletion in patients on hemodialysis. Plasma depletion of ergothioneine reduces the amount available for uptake into various tissues, including erythrocytes where ergothioneine is normally highly concentrated. Indeed, we had previously found that the erythrocyte ergothioneine levels in patients on hemodialysis were < 10% of those of control participants.⁷ This study extended our investigation of ergothioneine depletion to patients on PD. We hypothesized that PD would deplete ergothioneine but not to the extent observed in patients on hemodialysis.

Methods

Recruitment and Sample Collection

Three groups of participants >18 years were recruited: 16 on PD, 16 on thrice-weekly hemodialysis, and 15 with no known kidney disease (controls). Patients on PD were recruited from the dialysis centers of US Renal Care if they were maintained on daily treatment for at least 2 months. They provided samples of blood, spent dialysate, and 24-hour urine (if present) at a routine clinic visit. Patients on hemodialysis were recruited from the dialysis centers of the Veterans Affairs Palo Alto and the Santa Clara Valley Medical Center if they were maintained on thrice-weekly treatment and were anuric (as defined by a reported urine output <1 cup per day). They provided pretreatment blood samples at a midweek treatment. Posttreatment blood samples and waste dialysate samples were also collected from 11 of the 16 patients on hemodialysis.⁷ Controls were staff at the Veterans Affairs Palo Alto and were eligible if they reported no known kidney disease. We recruited controls with a similar age range and proportion of males and females that would match with the patients on dialysis in an effort to eliminate potential effects of age and sex on ergothioneine levels. They provided a nonfasting blood sample. Samples from 12 of the patients on PD, eleven of the patients on hemodialysis, and 12 of the controls have been used in previous studies.⁷ We did not attempt to match patients on PD and hemodialysis. The study was approved by the Institutional Review Boards of Stanford University and Santa Clara Valley Medical Center and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants.

Solute Measurements and Calculations

Aliquots of whole blood, plasma, urine, and dialysate were stored at −80°C until analysis. Ergothioneine was measured using liquid chromatography-tandem mass spectrometry with stable isotope dilution as previously described.⁷ Urea nitrogen and creatinine in the plasma, urine, and dialysate were measured by the clinical laboratory.

We measured ergothioneine levels in both the whole blood and plasma. Whole blood levels allowed for calculation of ergothioneine levels in the erythrocytes, a tissue site where ergothioneine is normally highly concentrated. Erythrocyte ergothioneine levels [RBC] were calculated as

$$\left[RBC\right]=\frac{\left[WB\right]-\left(\left(1-Hct\right)\hspace{0.17em}x\hspace{0.17em}\left[Plasma\right]\right)}{Hct}$$ (1)

where [WB] is the ergothioneine concentration in whole blood, Hct is hematocrit, and [Plasma] is ergothioneine concentration in plasma. For the patients on PD and hemodialysis, the hematocrit values from routine clinical assessment were used. For the controls, the hematocrit was assumed to be 45% for male participants and 40.5% for female participants on the basis of the National Health and Nutrition Examination Survey because their hematocrit levels were not measured.¹⁷

Solute levels measured in patients on daily PD were considered to be close to time-averaged levels. Time-averaged PD clearance was calculated as the dialytic removal rate divided by the plasma level of each solute. Residual kidney clearance for the patients on PD who still produced urine was calculated as the urinary excretion rate divided by the plasma level of each solute. Hemodialytic clearance was calculated as the dialytic removal rate divided by the logarithmic mean of the pretreatment and posttreatment plasma levels of each solute. Time-averaged hemodialytic clearance was calculated as the clearance multiplied by the fraction of the week on hemodialysis.

Statistical Analysis

Comparisons among the PD, hemodialysis, and control groups were performed using ANOVA, with significance of pairwise comparisons using the Tukey method and adjusted for multiple comparisons using the Bonferroni method. Erythrocyte and plasma levels of ergothioneine were log transformed before comparison. Comparisons between the PD and hemodialysis groups were performed using the Mann–Whitney U test. Comparisons of clearance among the solutes urea, creatinine, and ergothioneine were performed using repeated measures ANOVA and adjusted for multiple comparisons using the Bonferroni test. Association of ergothioneine levels with residual urea clearance and with dialysis vintage was assessed using linear regression. Statistical analysis was performed using SPSS v29.

Results

Table 1 summarizes the characteristics of the patients on PD, patients on hemodialysis, and controls. The age, sex, weight, and body surface area were similar among the three groups. The dialysis vintage ranged widely but was not significantly different between the patients on PD and hemodialysis. Laboratory values for the patients on PD and hemodialysis were from their routine clinical assessments extracted from the medical chart. For the patients on PD, laboratory values were from samples obtained during a routine adequacy assessment. For the patients on hemodialysis, laboratory values were from samples obtained pretreatment during the first of three treatments of the week. The plasma creatinine and urea nitrogen levels of the patients on dialysis were higher than those of the controls but were not different between the patients on PD and hemodialysis. There was also no difference in the laboratory values of hemoglobin, albumin, and phosphorus between the patients on PD and hemodialysis. The weekly total stdKt/V_urea of the patients on PD was lower than that of the patients on hemodialysis. Among the patients on PD, residual function provided a stdKt/V_urea of 0.57±0.57 of the average total stdKt/V_urea of 1.96±0.46. Four patients on PD were anuric, and 12 had residual urea clearance averaging 3.1±2.6 ml/min. 13 performed automated PD using a cycler overnight with 4.0±1.2 cycles per night and 2.1±0.3 L per cycle. Seven of the patients on automated PD also performed one daytime dwell with 1.7±0.6 L. Three patients performed continuous ambulatory PD with 2.7±0.6 cycles per day and 2.1±0.3 L per cycle. The prescription parameters for the patients on hemodialysis are summarized in Supplemental Table 1.

Table 1.

Characteristics

Characteristic	PD (n=16)	Hemodialysis (n=16)	Control (n=15)	P Values
				PD Versus Hemodialysis	PD Versus Control	Hemodialysis Versus Control
Age (yr)	60±17	63±10	59±12	1.0	1.0	1.0
Sex (M/F)	11/5	12/4	11/4	1.0	1.0	1.0
Weight (kg)	68±16	76±21	77±14	1.0	1.0	1.0
BSA (m2)	1.78±0.27	1.81±0.25	1.92±0.19	1.0	0.77	1.0
Dialysis vintage (mo)	27±24	54±62	—	0.35	—	—
Laboratory values
Creatinine (mg/dl)	9.7±4.4	9.5±2.7	0.92±0.21	1.0	<0.001	<0.001
Urea nitrogen (mg/dl)	59±13	76±15	16±4	0.38	<0.001	<0.001
Hemoglobin (g/dl)	10.2±1.2	10.0±1.1	—	0.13	—	—
Albumin (g/dl)	3.8±0.3	4.0±0.3	—	0.16	—	—
Phosphorus (mg/dl)	5.6±1.2	5.7±1.6	—	0.81	—	—
stdKt/Vurea (total)	1.96±0.46	2.25±0.17	—	0.011	—	—
stdKt/Vurea (dialytic)	1.41±0.57	2.25±0.17	—	<0.001	—	—
stdKt/Vurea (residual)	0.57±0.57	-	—	—	—	—

Results are mean±SD. Hemoglobin, albumin, and phosphorus were not measured in the controls. Laboratory values for the patients on peritoneal dialysis and hemodialysis were from their routine clinical assessments extracted from the medical chart. For the patients on peritoneal dialysis, laboratory values were from samples obtained during a routine adequacy assessment. For the patients on hemodialysis, laboratory values were from samples obtained pretreatment during the first of three treatments of the week (either Monday or Tuesday). The stdKt/V_urea values for patients on hemodialysis were calculated using Solute Solver,³¹ which is based on the equations provided in the Kidney Disease Outcomes Quality Initiative Clinical Practice Guideline for Hemodialysis Adequacy: 2015 update³² (Supplemental Methods). BSA, body surface area; PD, peritoneal dialysis.

Erythrocyte and plasma levels of ergothioneine are summarized in Table 2. Erythrocyte ergothioneine levels in both the patients on PD and hemodialysis were significantly lower than those in the controls (PD: 190±102 μM, hemodialysis: 55±34 μM, and controls: 556±577 μM). However, the erythrocyte levels were not as low in the patients on PD as in the patients on hemodialysis. Plasma ergothioneine levels in both groups of patients on dialysis were also lower than those in controls, but to a lesser extent than the erythrocyte levels (PD: 0.67±0.30 μM, hemodialysis: 0.47±0.20 μM, and controls: 2.1±1.6 μM). Plasma levels in the patients on PD were not significantly greater than pretreatment plasma levels in patients on hemodialysis. As has previously been reported, comparison of erythrocyte and plasma ergothioneine levels shows that ergothioneine is highly concentrated in erythrocytes.^7,18 We observed an average erythrocyte-to-plasma concentration ratio >100 in each group (PD: 283±82, hemodialysis: 122±53, and controls: 241±69). The ratio was no different in the patients on PD and controls but was lower in the patients on hemodialysis who had lower erythrocyte levels. Comparison of ergothioneine levels between PD and hemodialysis is based on conventional pretreatment assessment of solute levels in hemodialysis. Measurement in a subset of eleven patients on hemodialysis showed that plasma ergothioneine levels decreased markedly during dialysis, suggesting that time-averaged plasma levels in patients on hemodialysis are lower than pretreatment levels (Supplemental Table 2). A lower time-averaged plasma level would result in the calculation of a higher erythrocyte-to-plasma concentration ratio. Although plasma levels of ergothioneine declined with hemodialysis, there was no reduction in blood ergothioneine levels posttreatment (Supplemental Table 3).

Table 2.

Ergothioneine measurements in erythrocytes and plasma

Ergothioneine Measurement	PD (n=16)	Hemodialysis (n=16)	Control (n=15)	P values
				PD Versus Hemodialysis	PD Versus Control	Hemodialysis Versus Control
Erythrocyte (μM)	190±102	55±34	556±577	<0.001	0.018	<0.001
Plasma (μM)	0.67±0.30	0.47±0.20	2.1±1.6	0.74	<0.001	<0.001
Erythrocyte/plasma ratio	283±82	122±53	241±69	<0.001	0.66	<0.001

Results are mean±SD. Erythrocyte levels were calculated as erythrocyte μM/L of erythrocyte water. PD, peritoneal dialysis.

The measured clearances by PD and hemodialysis of ergothioneine were compared with those of the routinely measured solutes urea and creatinine, as summarized in Table 3 and Supplemental Figure 1. Solutes were cleared by both dialysis and the residual kidneys in the patients on PD. PD provided the highest clearance for urea, followed by creatinine and then ergothioneine (urea: 5.3±1.8 ml/min, creatinine: 3.5±1.6 ml/min, and ergothioneine: 2.6±1.0 ml/min). The residual kidneys maintained contributions to the total clearance of urea and creatinine but contributed much less to the total clearance of ergothioneine, consistent with tubular reabsorption of ergothioneine by the kidneys. The combination of PD and residual kidney contributions to solute clearance, therefore, resulted in similar total clearance between urea and creatinine but a much lower total clearance for ergothioneine (urea: 7.6±2.8 ml/min, creatinine: 7.8±6.8 ml/min, and ergothioneine: 2.9±1.0 ml/min). As expected, hemodialysis provided a higher clearance for urea than both creatinine and ergothioneine. In contrast to PD, the clearance of ergothioneine by hemodialysis was similar to that of creatinine. The relation of a solute's mol wt on PD versus hemodialysis clearance is further illustrated in Supplemental Figure 1. Neither erythrocyte nor plasma ergothioneine levels were associated with the residual urea clearance in the patients on PD, as illustrated in Figure 1. Erythrocyte and plasma ergothioneine levels were not associated with dialysis vintage in the patients on either PD or hemodialysis (Supplemental Figure 2).

Table 3.

Clearance of ergothioneine, urea, and creatinine

Solute	Clearance
	PD			Hemodialysis
	Dialytic Clearance (ml/min)	Residual Clearance (ml/min)	Total Clearance (ml/min)	Total Clearance (ml/min)
Urea	5.3±1.8a,b	2.3±2.6a,b	7.6±2.8b	14.5±3.0a,b
Creatinine	3.5±1.6c	4.4±6.8c	7.8±6.8c	8.3±2.3
Ergothioneine	2.6±1.0	0.36±0.48	2.9±1.0	8.6±2.5

Results are mean±SD. The clearance for hemodialysis is presented as the time-averaged (weekly) clearance. PD, peritoneal dialysis.

^aP < 0.05, urea versus creatinine.

^bP < 0.05, urea versus ergothioneine.

^cP < 0.05, creatinine versus ergothioneine.

Figure 1.

The relationship between ergothioneine levels and residual kidney urea clearance is shown. Left: erythrocyte; right: plasma.

Discussion

Both PD and hemodialysis lack the kidney's ability to reabsorb solutes in the tubules after they are filtered through the glomerulus. Valuable solutes may, therefore, be lost with both forms of dialysis treatment. Small solutes reported to be lost by PD are similar to those which may be depleted by hemodialysis, including carnitine, vitamins, and amino acids.² Although loss of these nutrients by PD is generally recognized, there are insufficient data to support specific supplementation.² Advances in analytic methods have allowed for the examination of a wider range of small solutes affected by dialysis. We previously found by metabolomic analysis that plasma ergothioneine levels were much lower in hemodialysis compared with controls.⁷ On the basis of that finding, we developed a quantitative liquid chromatography-mass spectrometry assay to confirm that ergothioneine was markedly depleted in patients on thrice-weekly hemodialysis.

The purpose of this study was to assess the extent to which ergothioneine was also depleted in patients on PD. Our studies of ergothioneine are motivated by evidence for its biologic value. Indeed, in vitro studies have demonstrated ergothioneine's ability to reduce injury from reactive oxygen species and radicals.⁹ In humans, it exists predominantly in the thione rather than thiol form (Supplemental Figure 3), which makes ergothioneine more resistant to autooxidation compared with antioxidant thiols such as GSH.⁸ Strong evidence for ergothioneine's value is the existence of a highly specific membrane transport protein, solute carrier SLC22A4, that takes ergothioneine up avidly in many tissues.¹⁴ SLC22A4 is abundantly expressed in the small intestine and absorbs ergothioneine from the diet. It is also abundant in the kidney tubule and reabsorbs ergothioneine filtered by the glomerulus, thereby preventing its loss in the urine.^7,18 In accord with its antioxidant activity, ergothioneine accumulates in areas that are susceptible to oxidative stress, such as erythrocytes, brain, and mitochondria.^8,19,20 Of note, ergothioneine is thought to be taken up by erythrocyte precursors rather than by mature erythrocytes.²¹ A second membrane protein SLC22A15 also transports ergothioneine.²² Although its affinity for ergothioneine is less than that of SLC22A4, SLC22A15 expression is higher in the brain, suggesting that it maintains cerebral ergothioneine levels. Because of its high abundance in the brain, studies have focused on ergothioneine's contribution to cognition and sleep. Its deficiency has been associated with neurologic disorders,⁸ and trials of ergothioneine supplementation in people without kidney disease showed improved measures of cognition after 1 year¹¹ and after 16 weeks¹² and improved measures of sleep after 16 weeks and after 4 weeks.^10,12,13,23

Insufficient antioxidant protection from ergothioneine deficiency could have particular ill effects in patients on dialysis. Because ergothioneine is highly concentrated in erythrocytes, it may play a role in the anemia of kidney disease. Erythrocytes are constantly exposed to reactive oxygen species and radicals that are produced from the interaction of hemoglobin with oxygen.^21,24 Excessive oxidative stress from ergothioneine deficiency may, therefore, shorten the lifespan of erythrocytes and exacerbate anemia. However, owing to our small study size and widely variable doses of erythropoietin-stimulating agents and iron for patients on both PD and hemodialysis, meaningful interpretation of the effect of erythrocyte ergothioneine levels on anemia could not be made. A larger study may provide more insight into whether higher ergothioneine levels will reduce the requirement for erythropoietin-stimulating agents and/or iron. Peritoneal membrane failure has also been linked to oxidative injury. Although this has largely been attributed to exposure to dialysate solution components including particularly glucose, insufficient antioxidant protection from ergothioneine depletion might also contribute.²⁵

Our previous study found that the ergothioneine removal by dialysis could account for the marked ergothioneine depletion in patients on hemodialysis.⁷ Our study showed that ergothioneine is also depleted in patients on PD. The degree of depletion, however, is less than in patients on hemodialysis. Analysis of our data suggests that lesser depletion of ergothioneine in patients on PD can be accounted for by incorporation of residual kidney function into the dialysis prescription with PD and by differences in solute clearances achieved with standard prescription of the two modalities. First, residual function is routinely incorporated into the dialysis prescription for PD but still often ignored in prescribing hemodialysis. Incorporation of residual urea clearance allows patients on PD to achieve target total weekly urea clearance with lesser dialytic urea clearance. However, owing to tubular reabsorption of ergothioneine, the residual kidney does not effectively clear ergothioneine. We would thus expect that to the extent physicians prescribe lower weekly exchange volumes for patients on PD with residual function, these patients would be less subject to ergothioneine depletion. In this study, however, we did not observe a tendency toward higher ergothioneine levels in patients with greater residual function as shown in Figure 1. The hypothesized relation of ergothioneine levels to residual function was presumably obscured by a wide variation in dietary ergothioneine intake, impaired intestinal absorption of ergothioneine, which has been reported in CKD, and/or nonrenal mechanisms of ergothioneine clearance that remain ill defined.^15,16,26

With dialysis prescriptions on the basis of urea kinetics, we would also expect to observe lesser average depletion of ergothioneine in PD than in patients on hemodialysis in the absence of residual function. Gotch²⁷ developed stdKt/V_urea on the basis of the concept that relatively stable plasma urea levels achieved with PD should be equal to the average of the pretreatment peak urea levels achieved by hemodialysis. This required hemodialysis to provide a considerably higher time-averaged urea clearance than PD. Other factors being equal, hemodialysis would thus achieve lower time-averaged plasma urea levels than PD. In addition, the dialytic clearance of ergothioneine relative to urea is lower with PD than with hemodialysis, consistent with the greater limitation that solute size imposes on peritoneal than on hemodialytic clearance.^28,29 Early hemodialysis prescriptions provided lower solute clearance than PD as solute size increased. However, advances in membrane technology allowed higher hemodialysis clearance with increasing solute size, whereas PD clearance for larger solutes remained low.²⁸ Thus, we found that the hemodialytic clearances of ergothioneine (mass 229 Da) and creatinine (mass 113 Da) were similar although lower than the hemodialytic clearance of urea which is removed from erythrocytes as blood passes through the dialyzer.³⁰ By contrast, the peritoneal dialytic clearance of ergothioneine was much lower than that of creatinine and proportionally lower than the peritoneal dialytic clearance of urea (Supplemental Figure 1). We would thus expect the time-averaged plasma ergothioneine levels to be higher in patients on PD than in patients on hemodialysis even in the absence of residual function. Presuming that cellular uptake is dependent on time-averaged plasma levels, this would lead to lesser ergothioneine depletion in erythrocytes and other tissues in PD than in patients on hemodialysis.

Our study has important limitations. We did not assess the contribution of ergothioneine depletion to adverse effects of kidney failure. We also did not assess the extent to which impaired intestinal absorption contributes to ergothioneine depletion in patients on dialysis. Given the wide variation in ergothioneine levels, a much larger study would be required to test the hypothesis that incorporation of residual function into the dialysis prescription limits the degree of ergothioneine depletion. We did not obtain samples over time between hemodialysis treatments of patients and, therefore, cannot confidently compare plasma ergothioneine levels in patients on PD with time-averaged plasma ergothioneine levels in patients on hemodialysis. We also did not measure hematocrit values in the control participants and, therefore, calculated their erythrocyte ergothioneine levels using hematocrit values from National Health and Nutrition Examination Survey data. Although the dialysis vintage was similar for the patients on PD and hemodialysis in this study, a larger study may show that longer time spent on either modality would pose increased risk of ergothioneine depletion.

In conclusion, the antioxidant ergothioneine is depleted in patients on PD but not to the degree seen in patients on hemodialysis. Solute depletion is a risk for both PD and hemodialysis, but because solute clearance by PD is lower, the depletion may not be as striking. Studies of ergothioneine repletion in patients on dialysis are required to confirm ergothioneine's benefits.

Supplementary Material

kidney360-7-842-s001.pdf ^{(1.9MB, pdf)}

kidney360-7-842-s002.pdf ^{(228.5KB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B447.

Author Contributions

Conceptualization: Tammy L. Sirich.

Data curation: Graham E. Abra, Lindsey S. Keo, Nhat M. Pham, Tammy L. Sirich, Josef K. Suba, Margaret K. Yu.

Formal analysis: Graham E. Abra, Lindsey S. Keo, Nhat M. Pham, Tammy L. Sirich, Josef K. Suba, Margaret K. Yu.

Funding acquisition: Tammy L. Sirich.

Investigation: Graham E. Abra, Lindsey S. Keo, Nhat M. Pham, Tammy L. Sirich, Josef K. Suba, Margaret K. Yu.

Methodology: Graham E. Abra, Nhat M. Pham, Tammy L. Sirich, Josef K. Suba, Margaret K. Yu.

Project administration: Nhat M. Pham, Tammy L. Sirich.

Supervision: Tammy L. Sirich.

Writing – original draft: Tammy L. Sirich.

Writing – review & editing: Graham E. Abra, Lindsey S. Keo, Nhat M. Pham, Tammy L. Sirich, Josef K. Suba, Margaret K. Yu.

Funding

T.L. Sirich: National Institutes of Health (R01 DK118426, R01 NS054791).

Declarative Statements

This study includes clinical experimentation and received Institutional Review Board or Ethics Committee approval. All patients provided written informed consent. This study includes clinical experimentation and complies with the Declaration of Helsinki.

Data Availability Statements

Original data generated for the study will be made available upon reasonable request to the corresponding author. Data Type: Raw Data/Source Data. Reason for Restricted Access: Deidentified participant data will be made available at the time of publication to investigators who provide a methodologically sound proposal which has been approved by an independent review committee. Proposals should be submitted to tsirich@stanford.edu.

Supplemental Material

This article contains the following supplemental material online at http://links.lww.com/KN9/B448.

Supplemental Table 1. Hemodialysis prescription parameters.

Supplemental Table 2. Time-averaged plasma levels of ergothioneine.

Supplemental Table 3. Effect of hemodialysis on ergothioneine levels.

Supplemental Figure 1. Solute clearance versus mol wt.

Supplemental Figure 2. Association of ergothioneine levels with dialysis vintage.

Supplemental Figure 3. Structure of ergothioneine.

Supplemental References.