The Removal of Uremic Solutes by Peritoneal Dialysis.

ABSTRACT: Peritoneal dialysis (PD) is now commonly prescribed to achieve target clearances for urea or creatinine. The International Society for Peritoneal Dialysis has proposed however that such targets should no longer be imposed. The Society's new guidelines suggest rather that the PD prescription should be adjusted to achieve well-being in individual patients. The relaxation of treatment targets could allow increased use of PD. Measurement of solute levels in patients receiving dialysis individualized to relieve uremic symptoms could also help us identify the solutes responsible for those symptoms and then devise new means to limit their accumulation. This possibility has prompted us to review the extent to which different uremic solutes are removed by PD.

Removal of Uremic Solutes from Dialysate by Activated Carbon.

BACKGROUND AND OBJECTIVES: Adsorption of uremic solutes to activated carbon provides a potential means to limit dialysate volumes required for new dialysis systems. The ability of activated carbon to take up uremic solutes has, however, not been adequately assessed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Graded volumes of waste dialysate collected from clinical hemodialysis treatments were passed through activated carbon blocks. Metabolomic analysis assessed the adsorption by activated carbon of a wide range of uremic solutes. Additional experiments tested the ability of the activated carbon to increase the clearance of selected solutes at low dialysate flow rates. RESULTS: Activated carbon initially adsorbed the majority, but not all, of 264 uremic solutes examined. Solute adsorption fell, however, as increasing volumes of dialysate were processed. Moreover, activated carbon added some uremic solutes to the dialysate, including methylguanidine. Activated carbon was particularly effective in adsorbing uremic solutes that bind to plasma proteins. In vitro dialysis experiments showed that introduction of activated carbon into the dialysate stream increased the clearance of the protein-bound solutes indoxyl sulfate and p-cresol sulfate by 77%±12% (mean±SD) and 73%±12%, respectively, at a dialysate flow rate of 200 ml/min, but had a much lesser effect on the clearance of the unbound solute phenylacetylglutamine. CONCLUSIONS: Activated carbon adsorbs many but not all uremic solutes. Introduction of activated carbon into the dialysate stream increased the clearance of those solutes that it does adsorb.

Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes.

Gut microbiota metabolism of dietary compounds generates a vast array of microbiome-dependent metabolites (MDMs), which are highly variable between individuals. The uremic MDMs (uMDMs) phenylacetylglutamine (PAG), p-cresol sulfate (PCS), and indoxyl sulfate (IS) accumulate during renal failure and are associated with poor outcomes. Targeted dietary interventions may reduce toxic MDM generation; however, it is unclear if inter-individual differences in diet or gut microbiome dominantly contribute to MDM variance. Here, we use a 7-day homogeneous average American diet to standardize dietary precursor availability in 21 healthy individuals. During dietary homogeneity, the coefficient of variation in PAG, PCS, and IS (primary outcome) did not decrease, nor did inter-individual variation in most identified metabolites; other microbiome metrics showed no or modest responses to the intervention. Host identity and age are dominant contributors to variability in MDMs. These results highlight the potential need to pair dietary modification with microbial therapies to control MDM profiles.

Improving Solute Clearances by Hemodialysis.

The adequacy of hemodialysis is now assessed by measuring the removal of the single-solute urea. The urea clearance provided by contemporary dialysis is a large fraction of the blood flow through the dialyzer and therefore cannot be increased much further. Other solutes however likely contribute more than urea to the residual uremic illness suffered by hemodialysis patients. We here review methods which could be employed to increase the clearance of nonurea solutes. We will separately consider the clearances of free low-molecular-mass solutes, free larger solutes, and protein-bound solutes. New clinical studies will be required to test the extent to which increasing the clearance on nonurea solutes with these various characteristics can improve patients' health.

Impaired Tubular Secretion of Organic Solutes in Advanced Chronic Kidney Disease.

BACKGROUND: The clearance of solutes removed by tubular secretion may be altered out of proportion to the GFR in CKD. Recent studies have described considerable variability in the secretory clearance of waste solutes relative to the GFR in patients with CKD. METHODS: To test the hypothesis that secretory clearance relative to GFR is reduced in patients approaching dialysis, we used metabolomic analysis to identify solutes in simultaneous urine and plasma samples from 16 patients with CKD and an eGFR of 7±2 ml/min per 1.73 m2 and 16 control participants. Fractional clearances were calculated as the ratios of urine to plasma levels of each solute relative to those of creatinine and urea in patients with CKD and to those of creatinine in controls. RESULTS: Metabolomic analysis identified 39 secreted solutes with fractional clearance >3.0 in control participants. Fractional clearance values in patients with CKD were reduced on average to 65%±27% of those in controls. These values were significantly lower for 18 of 39 individual solutes and significantly higher for only one. Assays of the secreted anions phenylacetyl glutamine, p-cresol sulfate, indoxyl sulfate, and hippurate confirmed variable impairment of secretory clearances in advanced CKD. Fractional clearances were markedly reduced for phenylacetylglutamine (4.2±0.6 for controls versus 2.3±0.6 for patients with CKD; P<0.001), p-cresol sulfate (8.6±2.6 for controls versus 4.1±1.5 for patients with CKD; P<0.001), and indoxyl sulfate (23.0±7.3 versus 7.5±2.8; P<0.001) but not for hippurate (10.2±3.8 versus 8.4±2.6; P=0.13). CONCLUSIONS: Secretory clearances for many solutes are reduced more than the GFR in advanced CKD. Impaired secretion of these solutes might contribute to uremic symptoms as patients approach dialysis.

Association of Plasma Uremic Solute Levels with Residual Kidney Function in Children on Peritoneal Dialysis.

BACKGROUND AND OBJECTIVES: Residual native kidney function confers health benefits in patients on dialysis. It can facilitate control of extracellular volume and inorganic ion concentrations. Residual kidney function can also limit the accumulation of uremic solutes. This study assessed whether lower plasma concentrations of uremic solutes were associated with residual kidney function in pediatric patients on peritoneal dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Samples were analyzed from 29 pediatric patients on peritoneal dialysis, including 13 without residual kidney function and ten with residual kidney function. Metabolomic analysis by untargeted mass spectrometry compared plasma solute levels in patients with and without residual kidney function. Dialytic and residual clearances of selected solutes were also measured by assays using chemical standards. RESULTS: Metabolomic analysis showed that plasma levels of 256 uremic solutes in patients with residual kidney function averaged 64% (interquartile range, 51%-81%) of the values in patients without residual kidney function who had similar total Kt/Vurea. The plasma levels were significantly lower for 59 of the 256 solutes in the patients with residual kidney function and significantly higher for none. Assays using chemical standards showed that residual kidney function provides a higher portion of the total clearance for nonurea solutes than it does for urea. CONCLUSIONS: Concentrations of many uremic solutes are lower in patients on peritoneal dialysis with residual kidney function than in those without residual kidney function receiving similar treatment as assessed by Kt/Vurea.

Precision medicine in transplantation and hemodialysis.

In kidney transplantation, precision medicine has already entered clinical practice. Donor and recipient human leucocyte antigen (HLA) regions are genotyped in two class 1 and usually three class 2 loci, and the individual degree of sensitization against alloimmune antigens is evaluated by the detection of anti-HLA donor-specific antibodies. Recently, the contribution of non-HLA mismatches to outcomes such as acute T- and B-cell-mediated rejection and even long-term graft survival was described. Tracking of specific alloimmune T- and B-cell clones by next generation sequencing and refinement of the immunogenicity of allo-epitopes specifically in the interaction with HLA and T- and B-cell receptors may further support individualized therapy. Although the choices of maintenance immunosuppression are rather limited, individualization can be accomplished by adjustment of dosing based on these risk predictors. Finally, supplementing histopathology by a transcriptomics analysis allows for a biological interpretation of the histological findings and avoids interobserver variability of results. In contrast to transplantation, the prescription of hemodialysis therapy is far from precise. Guidelines do not consider modifications by age, diet or many comorbid conditions. Patients with residual kidney function routinely receive the same treatment as those without. A major barrier hitherto is the definition of 'adequate' treatment based on urea removal. Kt/Vurea and related parameters neither reflect the severity of uremic symptoms nor predict long-term outcomes. Urea is poorly representative for numerous other compounds that accumulate in the body when the kidneys fail, yet clinicians prescribe treatment based on its measurement. Modern technology has provided the means to identify other solutes responsible for specific features of uremic illness and their measurement will be a necessary step in moving beyond the standardized prescription of hemodialysis.

Metabolomic analysis of uremic pruritus in patients on hemodialysis.

Pruritus is a common debilitating symptom experienced by hemodialysis patients. Treatment is difficult because the cause of uremic pruritus is not known. This study addressed the hypothesis that pruritus is caused by solutes that accumulate in the plasma when the kidneys fail. We sought to identify solutes responsible for uremic pruritus using metabolomic analysis to compare the plasma of hemodialysis patients with severe pruritus versus mild/no pruritus. Pruritus severity in hemodialysis patients was assessed using a 100-mm visual analogue scale (VAS), with severe pruritus defined as >70 mm and mild/no pruritus defined as <10 mm. Twelve patients with severe pruritus (Itch) and 24 patients with mild/no pruritus (No Itch) were included. Pre-treatment plasma and plasma ultrafiltrate were analyzed using an established metabolomic platform (Metabolon, Inc.). To identify solutes associated with pruritus, we compared the average peak area of each solute in the Itch patients to that of the No Itch patients using the false discovery rate (q value) and principal component analysis. Dialysis vintage, Kt/Vurea, and serum levels of calcium, phosphorus, PTH, albumin, ferritin, and hemoglobin were similar in the Itch and No Itch patients. Metabolomic analysis identified 1,548 solutes of which 609 were classified as uremic. No difference in the plasma or plasma ultrafiltrate levels of any solute or group of solutes was found between the Itch and No Itch patients. Metabolomic analysis of hemodialysis patients did not reveal any solutes associated with pruritus. A limitation of metabolomic analysis is that the solute of interest may not be included in the metabolomic platform's chemical library. A role for uremic solutes in pruritus remains to be established.

Improving Clearance for Renal Replacement Therapy.

The adequacy of hemodialysis is now assessed by measuring the removal of a single solute, urea. The urea clearance provided by current dialysis methods is a large fraction of the blood flow through the dialyzer, and, therefore, cannot be increased much further. However, other solutes, which are less effectively cleared than urea, may contribute more to the residual uremic illness suffered by patients on hemodialysis. Here, we review a variety of methods that could be used to increase the clearance of such nonurea solutes. New clinical studies will be required to test the extent to which increasing solute clearances improves patients' health.

Why Is the GFR So High?: Implications for the Treatment of Kidney Failure.

The high GFR in vertebrates obligates large energy expenditure. Homer Smith's teleologic argument that this high GFR was needed to excrete water as vertebrates evolved in dilute seas is outdated. The GFR is proportional to the metabolic rate among vertebrate species and higher in warm-blooded mammals and birds than in cold-blooded fish, amphibians, and reptiles. The kidney clearance of some solutes is raised above the GFR by tubular secretion, and we presume secretion evolved to eliminate particularly toxic compounds. In this regard, high GFRs may provide a fluid stream into which toxic solutes can be readily secreted. Alternatively, the high GFR may be required to clear solutes that are too large or too varied to be secreted, especially bioactive small proteins and peptides. These considerations have potentially important implications for the understanding and treatment of kidney failure.

Impaired Tubular Secretion of Organic Solutes in Acute Kidney Injury.

BACKGROUND: Impairment of kidney function is routinely assessed by measuring the accumulation of creatinine, an organic solute cleared largely by glomerular filtration. We tested whether the clearance of solutes that undergo tubular secretion is reduced in proportion to the clearance of creatinine in humans with AKI. METHODS: Four endogenously produced organic solutes (phenylacetylglutamine [PAG], hippurate [HIPP], indoxyl sulfate [IS], and p-cresol sulfate [PCS]) were measured in spot urine and plasma samples from ten patients with AKI and 17 controls. Fractional clearance relative to creatinine was calculated to assess tubular secretion. Fractional clearance values were calculated in terms of the free, unbound levels of HIPP, IS, and PCS that bind to plasma proteins. RESULTS: Fractional clearance values for PAG, HIPP, IS, and PCS were >1.0 in patients with AKI as well as controls, indicating that these solutes were still secreted by the tubules of the injured kidneys. Fractional clearance values were, however, significantly lower in patients with AKI than controls, indicating that kidney injury reduced tubular secretion more than glomerular filtration (AKI versus control: PAG, 2.1±0.7 versus 4.6±1.4, P<0.001; HIPP, 10±5 versus 15±7, P=0.02; IS, 10±6 versus 28±7, P<0.001; PCS, 3.3±1.8 versus 10±3, P<0.001). Free plasma levels rose out of proportion to total plasma levels for each of the bound solutes in AKI, so that calculating their fractional clearance in terms of their total plasma levels failed to reveal their impaired secretion. CONCLUSIONS: Tubular secretion of organic solutes can be reduced out of proportion to glomerular filtration in AKI. Impaired secretion of protein-bound solutes may be more reliably detected when clearances are expressed in terms of their free, unbound levels in the plasma.

Contribution of 'clinically negligible' residual kidney function to clearance of uremic solutes.

BACKGROUND: Residual kidney function (RKF) is thought to exert beneficial effects through clearance of uremic toxins. However, the level of native kidney function where clearance becomes negligible is not known. METHODS: We aimed to assess whether levels of nonurea solutes differed among patients with 'clinically negligible' RKF compared with those with no RKF. The hemodialysis study excluded patients with urinary urea clearance >1.5 mL/min, below which RKF was considered to be 'clinically negligible'. We measured eight nonurea solutes from 1280 patients participating in this study and calculated the relative difference in solute levels among patients with and without RKF based on measured urinary urea clearance. RESULTS: The mean age of the participants was 57 years and 57% were female. At baseline, 34% of the included participants had clinically negligible RKF (mean 0.7 ± 0.4 mL/min) and 66% had no RKF. Seven of the eight nonurea solute levels measured were significantly lower in patients with RKF than in those without RKF, ranging from -24% [95% confidence interval (CI) -31 to -16] for hippurate, -7% (-14 to -1) for trimethylamine-N-oxide and -4% (-6 to -1) for asymmetric dimethylarginine. The effect of RKF on plasma levels was comparable or more pronounced than that achieved with a 31% higher dialysis dose (spKt/Vurea 1.7 versus 1.3). Preserved RKF at 1-year follow-up was associated with a lower risk of cardiac death and first cardiovascular event. CONCLUSIONS: Even at very low levels, RKF is not 'negligible', as it continues to provide nonurea solute clearance. Management of patients with RKF should consider these differences.

Plasma pseudouridine levels reflect body size in children on hemodialysis.

BACKGROUND: Dialysis in children as well as adults is prescribed to achieve a target spKt/Vurea, where Vurea is the volume of distribution of urea. Waste solute production may however be more closely correlated with body surface area (BSA) than Vurea which rises in proportion with body weight. Plasma levels of waste solutes may thus be higher in smaller patients when targeting spKt/Vurea since they have higher BSA relative to body weight. This study measured levels of pseudouridine (PU), a novel marker solute whose production is closely proportional to BSA, to test whether prescription of dialysis to a target spKt/Vurea results in higher plasma levels of PU in smaller children. METHODS: PU and urea nitrogen (ureaN) were measured in plasma and dialysate at the midweek hemodialysis session in 20 pediatric patients, with BSA ranging from 0.65-1.87m2. Mathematical modeling was employed to estimate solute production rates and average plasma solute levels. RESULTS: The dialytic clearance (Kd) of PU was proportional to that of ureaN (average KdPU/KdUreaN 0.69 ± 0.13, r2 0.84, p < 0.001). Production of PU rose in proportion with BSA (r2 0.57, p < 0.001). The pretreatment plasma level of PU was significantly higher in smaller children (r2 0.20, p = 0.051) while the pretreatment level of ureaN did not vary with size. CONCLUSIONS: Prescribing dialysis based on urea kinetics may leave uremic solutes at higher levels in small children. Measurement of a solute produced proportional to BSA may provide a better index of dialysis adequacy than measurement of urea.

Accumulation of uremic solutes in the cerebrospinal fluid in experimental acute renal failure.

The accumulation of uremic solutes in kidney failure may impair mental function. The present study profiled the accumulation of uremic solutes in the cerebrospinal fluid (CSF) in acute renal failure. CSF and plasma ultrafiltrate were obtained from rats at 48 h after sham operation (control; n = 10) or bilateral nephrectomy (n = 10) and analyzed using an established metabolomic platform. Two hundred forty-eight solutes were identified as uremic based on their accumulation in the plasma ultrafiltrate of nephrectomized compared with control rats. CSF levels of 124 of these solutes were sufficient to allow calculation of CSF-to-plasma ultrafiltrate concentration ratios. Levels of many of the uremic solutes were normally lower in the CSF than in the plasma ultrafiltrate, indicating exclusion of these solutes from the brain. CSF levels of the great majority of the uremic solutes increased in renal failure. The increase in the CSF was, however, relatively less than in the plasma ultrafiltrate for most solutes. In particular, for the 31 uremic solutes with CSF-to-plasma ultrafiltrate ratios of <0.25 in control rats, the average CSF-to-plasma ultrafiltrate ratio decreased from 0.13 ± 0.07 in control rats to 0.09 ± 0.06 in nephrectomized rats, revealing sustained ability to exclude these solutes from the brain. In summary, levels of many uremic solutes are normally kept lower in the CSF than in the plasma ultrafiltrate by the action of the blood-brain and blood-CSF barriers. These barriers remain functional but cannot prevent accumulation of uremic solutes in the CSF when the kidneys fail.

Characteristics of Colon-Derived Uremic Solutes.

BACKGROUND AND OBJECTIVES: Colon microbial metabolism produces solutes that are normally excreted in the urine and accumulate in the plasma when the kidneys fail. This study sought to further identify and characterize human colon-derived uremic solutes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Colon-derived solutes normally excreted in the urine were identified by comparing urine from controls (n=17) and patients with total colectomies (n=12), using an established metabolomic platform. Colon-derived solutes that accumulate in kidney failure were then identified by comparing the plasma of the control patients with that of patients on dialysis (n=14). RESULTS: Ninety-one urinary solutes were classified as colon-derived on the basis of the finding of a urine excretion rate at least four-fold higher in control patients than in patients with total colectomies. Forty-six were solutes with known chemical structure, 35 of which had not previously been identified as colon-derived. Sixty of the colon-derived solutes accumulated in the plasma of patients with ESKD to a degree greater than urea and were therefore classified as uremic. The estimated urinary clearance for 27 out of the 32 colon-derived solutes for which clearance could be calculated exceeded that of creatinine, consistent with tubular secretion. Sulfatase treatment revealed that 42 out of the 91 colon-derived solutes detected were likely conjugates. CONCLUSIONS: Metabolomic analysis identified numerous colon-derived solutes that are normally excreted in human urine. Clearance by tubular secretion limits plasma levels of many colon-derived solutes.