Phosphorus metabolism in peritoneal dialysis- and haemodialysis-treated patients.

BACKGROUND: Phosphorus control is generally considered to be better in peritoneal dialysis (PD) patients as compared with haemodialysis (HD) patients. Predialysis phosphorus concentrations are misleading as a measure of phosphorus exposure in HD, as these neglect significant dialysis-related fluctuations. METHODS: Parameters of mineral metabolism, including parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23), were determined in 79 HD and 61 PD patients. In PD, phosphorus levels were determined mid-morning. In HD, time-averaged phosphorus concentrations were modelled from measurements before and after the mid-week dialysis session. Weekly renal, dialytic and total phosphorus clearances as well as total mass removal were calculated from urine and dialysate collections. RESULTS: Time-averaged serum phosphorus concentrations in HD (3.5 ± 1.0 mg/dL) were significantly lower than the mid-morning concentrations in PD (5.0 ± 1.4 mg/dL, P < 0.0001). In contrast, predialysis phosphorus concentrations (4.6 ± 1.4 mg/dL) were not different from PD. PTH and FGF-23 levels were significantly higher in PD. Despite higher residual renal function, total phosphorus clearance was significantly lower in PD (P < 0.0001). Total phosphorus mass removal, conversely, was significantly higher in PD (P < 0.05). CONCLUSIONS: Our data suggest that the time-averaged phosphorus concentrations in patients treated with PD are higher as compared with patients treated with HD. Despite a better preserved renal function, total phosphorus clearance is lower in patients treated with PD. Additional studies are needed to confirm these findings in a population with a different demographic profile and dietary background and to define clinical implications.

Effect of Treatment Duration and Frequency on Uremic Solute Kinetics, Clearances and Concentrations.

The kinetics of uremic solute clearances are discussed based on two categories of uremic solutes, namely those that are and those that are not derived directly from nutrient intake, particularly dietary protein intake. This review highlights dialysis treatments that are more frequent and longer (high-dose hemodialysis) than conventional thrice weekly therapy. It is proposed that the dialysis dose measures based on urea as a marker uremic solute, such as Kt/V and stdKt/V, be referred to as measures of dialysis inadequacy, not dialysis adequacy. For uremic solutes derived directly from nutrient intake, it is suggested that inorganic phosphorus and protein-bound uremic solutes be considered as markers in the development of alternative measures of dialysis dose for high-dose hemodialysis prescriptions. As the current gap in understanding the detailed kinetics of protein-bound uremic solutes, it is proposed that normalization of serum phosphorus concentration with a minimum (or preferably without a) need for oral-phosphorus binders be targeted as a measure of dialysis adequacy in high-dose hemodialysis. For large uremic solutes not derived directly from nutrient intake (middle molecules), use of extracorporeal clearances for ß2 -microglobulin that are higher than currently available during thrice weekly therapy is unlikely to reduce predialysis serum ß2 -microglobulin concentrations. High-dose hemodialysis prescriptions will lead to reductions in predialysis serum ß2 -microglobulin concentrations, but such reductions are also limited by significant residual kidney clearance. Kinetic data regarding middle molecules larger than ß2 -microglobulin are scarce; additional studies on such uremic solutes are of high interest to better understand improved methods for prescribing high-dose hemodialysis prescriptions to improve patient outcomes.

Heparin-coated dialyzer membranes: is non-inferiority good enough?

Evidence on the optimal anticoagulation regimen for hemodialysis in patients at high bleeding risk is scarce. The HepZero study is the first large multinational study comparing two different anticoagulation strategies to avoid systemic heparinization. The use of a heparin-coated dialysis membrane proved to be non-inferior to saline infusion. Superiority of either treatment, however, could not be demonstrated. These findings challenge current guidelines but equally raise questions on the choice of either strategy as compared with regional citrate anticoagulation.

Residual renal function is an independent determinant of serum FGF-23 levels in dialysis patients.

BACKGROUND: Both poor residual renal function (RRF) and high fibroblast growth factor 23 (FGF-23) levels are associated with arterial stiffness, left ventricular hypertrophy and increased (cardiovascular) mortality. Whether FGF-23 and RRF are interrelated is unknown. METHODS: We performed a prospective observational cohort study in 35 peritoneal dialysis (PD) patients with evaluation at 1, 6, 12 and 24 months after start of PD. In addition, the role of RRF was assessed in a cross-sectional observational cohort study including 68 prevalent haemodialysis patients. RESULTS: RRF significantly declined over time in PD patients. This decline was parallelled by a significant increase of both serum phosphorus and FGF-23 levels. In the prevalent dialysis cohort, RRF was found to be inversely associated with serum FGF-23 levels, independent of dialysis vintage, dialytic creatinine clearance, estimates of dietary phosphate intake (i.e. normalized protein nitrogen appearance), active vitamin D therapy and serum phosphorus and calcium levels. RRF, serum phosphorus and calcium levels and active vitamin D therapy explain 69% of the variation in FGF-23. The 38 anuric patients had higher FGF-23 levels but similar serum phosphorus levels. CONCLUSIONS: We demonstrate an important association between RRF and FGF-23, independent of classical determinants. This favours the hypothesis that the ailing kidney directly contributes to the raised FGF-23 levels. Whether FGF-23 is associated with poor outcomes independent of RRF, or vice versa, remains to be clarified.

p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin.

INTRODUCTION: Protein-bound uraemic retention solutes, including p-cresyl sulfate and indoxyl sulfate, contribute substantially to the uraemic syndrome. These and several other uraemic retention solutes originate from intestinal bacterial protein fermentation. We investigated whether the prebiotic oligofructose-enriched inulin reduced serum concentration of p-cresyl sulfate and indoxyl sulfate, through interference with intestinal generation. METHODS: We performed a single centre, non-randomized, open-label phase I/II study in maintenance HD patients with a 4-week, escalating dose regimen of oligofructose-enriched inulin (ORAFTI Synergy 1, Tienen, Belgium) (www.clinicaltrials.gov NCT00695513). Changes in p-cresyl sulfate and indoxyl sulfate serum concentrations as well as changes in p-cresyl sulfate and indoxyl sulfate generation rates were analysed. RESULTS: Compliance with therapy was excellent. p-Cresyl sulfate serum concentrations at 4 weeks were significantly reduced by 20% (intention to treat, P = 0.01; per protocol, P = 0.03). Also p-cresyl sulfate generation rates were reduced (P = 0.007). In contrast, neither indoxyl sulfate generation rates (P = 0.9) nor serum concentrations (P = 0.4) were significantly changed. CONCLUSION: The prebiotic oligofructose-inulin significantly reduced p-cresyl sulfate generation rates and serum concentrations in haemodialysis patients. Whether reduction of p-cresyl sulfate serum concentrations, an independent predictor of cardiovascular disease in HD patients, will result in improved cardiovascular outcomes remains to be proven.

The uremic retention solute p-cresyl sulfate and markers of endothelial damage.

BACKGROUND: Cardiovascular disease is highly prevalent in patients with chronic kidney disease. In hemodialysis patients, the protein-bound uremic retention solute p-cresol is independently associated with cardiovascular disease. The underlying mechanisms have not been elucidated. STUDY DESIGN: (1) Prospective observational study of humans and (2) in vitro study in human umbilical vein endothelial cells. SETTING: Hemodialysis patients. FACTOR: p-Cresol and its main derivative p-cresyl sulfate. OUTCOMES: Endothelial dysfunction. MEASUREMENTS: We studied: (1) the relation between p-cresol and blood markers of endothelial dysfunction, including soluble P-selectin and endothelial microparticles; and (2) direct effects of p-cresol and p-cresyl sulfate on endothelial cell cultures. RESULTS: (1) In a cohort of 100 maintenance hemodialysis patients, free serum p-cresol concentrations (median, 11.7 micromol/L; interquartile range, 15.2) were directly associated with circulating endothelial microparticles (P = 0.007), but not with soluble P-selectin (mean, 37.7 +/- 14.4 [SD] pg/mL). Other independent determinants of the degree of circulating microparticles were greater serum phosphorus (mean, 4.8 +/- 1.5 mg/dL; P = 0.008) and serum calcium concentrations (mean, 9.3 +/- 0.8 mg/dL; P = 0.03), whereas treatment with active vitamin D (P = 0.008) and vintage (median, 25 months; P = 0.04) were inversely associated. (2) In vitro, p-cresyl sulfate induced a dose-dependent increase in the shedding of endothelial microparticles (P < 0.001) by human umbilical vein endothelial cells. Shedding was reduced, but not completely aborted, in the presence of albumin, whereas the selective Rho kinase inhibitor Y-27632 abrogated the p-cresyl sulfate-induced generation of endothelial microparticles. LIMITATIONS: The relationship between p-cresyl sulfate and shedding of endothelial microparticles in vivo was not mechanistically explored. CONCLUSION: p-Cresyl sulfate induces shedding of endothelial microparticles in the absence of overt endothelial damage in vitro and is independently associated with the number of endothelial microparticles in hemodialysis patients. These findings suggest that p-cresyl sulfate alters endothelial function in hemodialysis patients.

Uremic toxins originating from colonic microbial metabolism.

Numerous molecules, which are either excreted or metabolized by the kidney, accumulate in patients with chronic kidney disease (CKD). These uremic retention molecules (URMs), contributing to the syndrome of uremia, may be classified according to their site of origin, that is, endogenous metabolism, microbial metabolism, or exogenous intake. It is increasingly recognized that bacterial metabolites, such as phenols, indoles, and amines, may contribute to uremic toxicity. In vitro studies have implicated bacterial URMs in CKD progression, cardiovascular disease, and bone and mineral disorders. Furthermore, several observational studies have demonstrated a link between serum levels of bacterial URMs and clinical outcomes. Bacterial metabolism may therefore be an important therapeutic target in CKD. There is evidence that besides reduced renal clearance, increased colonic generation and absorption explain the high levels of bacterial URMs in CKD. Factors promoting URM generation and absorption include an increased ratio of dietary protein to carbohydrate due to insufficient intake of fiber and/or reduced intestinal protein assimilation, as well as prolonged colonic transit time. Two main strategies exist to reduce bacterial URM levels: interventions that modulate intestinal bacterial growth (e.g., probiotics, prebiotics, dietary modification) and adsorbent therapies that bind bacterial URMs in the intestines to reduce their absorption (e.g., AST-120, sevelamer). The efficacy and clinical benefit of these strategies are currently an active area of interest.

A review of albumin binding in CKD.

Hypoalbuminemia is associated with excess mortality in patients with kidney disease. Albumin is an important oxidant scavenger and an abundant carrier protein for numerous endogenous and exogenous compounds. Several specific binding sites for anionic, neutral, and cationic ligands were described. Overall, the extent of binding depends on the ligand and albumin concentration, albumin-binding affinity, and presence of competing ligands. Chronic kidney disease affects all these determinants. This may result in altered pharmacokinetics and increased risk of toxicity. Renal clearance of albumin-bound solutes mainly depends on tubular clearance. Dialytic clearance by means of conventional hemodialysis/hemofiltration and peritoneal dialysis is limited. Other epuration techniques combining hemodialysis with adsorption have been developed. However, the benefit of these techniques remains to be proved.

Haemodynamic or metabolic stimulation tests to reveal the renal functional response: requiem or revival?

Renal stimulation tests document the dynamic response of the glomerular filtration rate (GFR) after a single or a combination of stimuli, such as an intravenous infusion of dopamine or amino acids or an oral protein meal. The increment of the GFR above the unstimulated state has formerly been called the renal functional reserve (RFR). Although the concept of a renal reserve capacity has not withstood scientific scrutiny, the literature documenting renal stimulation merits renewed interest. An absent or a blunted response of the GFR after a stimulus indicates lost or diseased nephrons. This information is valuable in preventing, diagnosing and prognosticating acute kidney injury and pregnancy-related renal events as well as chronic kidney disease. However, before renal function testing is universally practiced, some shortcomings must be addressed. First, a common nomenclature should be decided upon. The expression of RFR should be replaced by renal functional response. Second, a simple protocol must be developed and propagated. Third, we suggest designing prospective studies linking a defective stimulatory response to emergence of renal injury biomarkers, to histological or morphological renal abnormalities and to adverse renal outcomes in different renal syndromes.

Serum concentrations of p-cresyl sulfate and indoxyl sulfate, but not inflammatory markers, increase in incident peritoneal dialysis patients in parallel with loss of residual renal function.

BACKGROUND: High serum concentrations of the protein-bound uremic retention solutes p-cresyl sulfate (PCS) and indoxyl sulfate (IndS) and inflammation are associated with increased cardiovascular morbidity and mortality in chronic kidney disease. Renal clearance contributes to up to 80% of the total clearance of PCS and IndS in peritoneal dialysis (PD) patients. Cross-sectional studies evaluating the impact of residual renal function (RRF) on serum concentrations of PCS, IndS, and circulating inflammatory markers have yielded conflicting results. ♢ METHODS: To clarify this issue, we carried out a prospective observational cohort study in incident PD patients (n = 35; 19 men; mean age: 55 ± 17 years). Midday blood samples were collected and analyzed for total serum PCS, IndS, C-reactive protein, and high-sensitivity interleukin 6. Peritoneal and renal clearances were calculated from urine and dialysate collections, and RRF was calculated as the mean of renal urea nitrogen and creatinine clearances. Patients were assessed 1, 6, 12, and 24 months after PD start. Differences between time points were analyzed using linear mixed models (LMMs). ♢ RESULTS: Residual renal function declined significantly over time (LMM p < 0.0001). Peritoneal clearances of both toxins tended to increase, but did not compensate for the declining renal clearances. Serum concentrations of PCS and IndS increased significantly over time (LMM p = 0.01; p = 0.0009). In contrast, total mass removal of both toxins remained stable. Circulating inflammatory markers did not change over time. ♢ CONCLUSIONS: Our data indicate that serum concentrations of PCS and IndS, but not inflammatory markers, increase in incident PD patients in parallel with loss of RRF.

Measuring total blood calcium displays a low sensitivity for the diagnosis of hypercalcemia in incident renal transplant recipients.

BACKGROUND AND OBJECTIVES: Hypercalcemia is a common complication in renal transplant recipients and has been associated with nephrocalcinosis and poor graft outcome. The performance of total calcium (tCa) in the diagnosis of blood calcium disturbances in renal transplant recipients is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compared the ability of total tCa concentration to identify low, normal, or high ionized calcium (iCa) concentration, i.e., the gold standard, in an unselected cohort of 268 renal transplant recipients. All patients were studied 3 and 12 months after successful engraftment. RESULTS: Hypercalcemia, defined as a iCa >1.29 mmol/L, was present in 58.6 and 44.8% of the patients at months 3 and 12, respectively. tCa concentrations >10.3 mg/dl, conversely, were observed in only 13.1% of the patients. Measuring tCa had a low sensitivity (20.3 and 24.2% at months 3 and 12, respectively) for the diagnosis of hypercalcemia. The agreement (κ coefficient [95% confidence interval]) between tCa concentrations and iCa was poor (month 3: 0.11 [0.05 to 0.17]; month 12: 0.20 [0.11 to 0.30]). The risk for underestimating iCa was increased by a low total bicarbonate concentration. Metabolic acidosis was observed in 48.1 and 37.3% of the patients at months 3 and 12, respectively. CONCLUSIONS: Total calcium greatly underestimates the diagnosis of hypercalcemia in incident renal transplant recipients. This is mainly explained by the high prevalence of metabolic acidosis in these patients.

p-Cresol and cardiovascular risk in mild-to-moderate kidney disease.

BACKGROUND AND OBJECTIVES: Cardiovascular disease is highly prevalent in chronic kidney disease. Traditional risk factors are insufficient to explain the high cardiovascular disease prevalence. Free p-cresol serum concentrations, mainly circulating as its derivative p-cresyl sulfate, are associated with cardiovascular disease in hemodialysis patients. It is not known if p-cresol is associated with cardiovascular disease in patients with chronic kidney disease not yet on dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a prospective observational study in 499 patients with mild-to-moderate kidney disease, we examined the multivariate association between p-cresol free serum concentrations and cardiovascular events. RESULTS: After a mean follow-up of 33 mo, 62 patients reached the primary end point of fatal or nonfatal cardiovascular events. Higher baseline concentrations of free p-cresol were directly associated with cardiovascular events (univariate hazard ratio [HR] 1.79, P<0.0001). In multivariate analysis, p-cresol remained a predictor of cardiovascular events, independent of GFR and independent of Framingham risk factors (full model, HR 1.39, P=0.04). CONCLUSIONS: These findings suggest that p-cresol measurements may help to predict cardiovascular disease risk in renal patients over a wide range of residual renal function, beyond traditional markers of glomerular filtration. Whether p-cresol is a modifiable cardiovascular risk factor in CKD patients remains to be proven.

Sodium octanoate to reverse indoxyl sulfate and p-cresyl sulfate albumin binding in uremic and normal serum during sample preparation followed by fluorescence liquid chromatography.

Indoxyl sulfate and p-cresyl sulfate are protein-bound marker molecules in chronic kidney disease. Recent findings suggest that indoxyl sulfate and p-cresyl sulfate directly contribute to the uremic syndrome. A method for quantification of p-cresyl sulfate and indoxyl sulfate total serum concentrations was developed. We used sodium octanoate as competitor to replace non-covalent binding of p-cresyl sulfate and indoxyl sulfate to albumin. Total, within-run, between-run and between-day imprecision for indoxyl sulfate and p-cresyl sulfate were all below 6%. The limit of quantification was 3.2microM for both analytes. Recovery, tested in hemodialysis patients, was 102% for indoxyl sulfate and 105% for p-cresyl sulfate. Deming regression demonstrated good agreement for indoxyl sulfate between this new method and an external HPLC method. Method comparison for p-cresyl sulfate of the new method with our in-house GC-MS method demonstrated good agreement, whereas method comparison with an external HPLC method revealed a small proportional bias. Sodium octanoate binding competition is a novel sample preparation that allows for direct quantification of indoxyl sulfate and p-cresyl sulfate.

p-Cresyl sulfate and indoxyl sulfate in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Indoxyl sulfate and p-cresyl sulfate are important representatives of the protein-bound uremic retention solutes. Serum levels of p-cresyl sulfate and indoxyl sulfate are linked to cardiovascular outcomes and chronic kidney disease progression, respectively. They share important features such as the albumin-binding site, low dialytic clearance, and both originate from protein fermentation. Whether serum concentrations are related is, however, not known. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In an observational study in 75 maintenance hemodialysis patients, we studied agreement between indoxyl sulfate and p-cresyl sulfate serum concentrations, dialytic reduction rates, and dialytic clearances. Concentrations were determined by HPLC. Dialytic clearances were determined from total spent dialysate collections. In vitro spiking experiments were performed to explore protein binding characteristics. RESULTS: Indoxyl sulfate and p-cresyl sulfate total serum concentrations were not related (r = 0.02, P = 0.9), whereas free serum concentrations were only moderately related (r = 0.53, P < 0.001). Indoxyl sulfate and p-cresyl sulfate share the same albumin binding site, for which they are competitive binding inhibitors. Intriguingly, indoxyl sulfate and p-cresyl sulfate reduction rates (r = 0.91, P < 0.001) and dialytic clearances (r = 0.97, P < 0.001) correlated tightly. CONCLUSIONS: Indoxyl sulfate and p-cresyl sulfate serum concentrations are not associated, suggesting different metabolic pathways. Indoxyl sulfate and p-cresyl sulfate are both valid markers to monitor behavior of protein-bound solutes during dialysis. Finally, they are competitive binding inhibitors for the same albumin binding site.

Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation.

BACKGROUND AND OBJECTIVES: In the first months after successful kidney transplantation, hypophosphatemia and renal phosphorus wasting are common and related to inappropriately high parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) levels. Little is known about the long-term natural history of renal phosphorus homeostasis in renal transplant recipients. DESIGN, SETTING, PARTICIPANTS: We prospectively followed parameters of mineral metabolism (including full-length PTH and FGF-23) in 50 renal transplant recipients at the time of transplantation (Tx), at month 3 (M3) and at month 12 (M12). Transplant recipients were (1:1) matched for estimated GFR with chronic kidney disease (CKD) patients. RESULTS: FGF-23 levels (Tx: 2816 [641 to 10665] versus M3: 73 [43 to 111] versus M12: 56 [34 to 78] ng/L, median [interquartile range]) and fractional phosphorus excretion (FE(phos); M3: 45 +/- 19% versus M12: 37 +/- 13%) significantly declined over time after renal transplantation. Levels 1 yr after transplantation were similar to those in CKD patients (FGF-23: 47 [34 to 77] ng/L; FE(phos) 35 +/- 16%). Calcium (9.1 +/- 0.5 versus 8.9 +/- 0.3 mg/dl) and PTH (27.2 [17.0 to 46.0] versus 17.5 [11.7 to 24.4] ng/L) levels were significantly higher, whereas phosphorus (3.0 +/- 0.6 versus 3.3 +/- 0.6 mg/dl) levels were significantly lower 1 yr after renal transplantation as compared with CKD patients. CONCLUSIONS: Data indicate that hyperphosphatoninism and renal phosphorus wasting regress by 1 yr after successful renal transplantation.

Protein-losing enteropathy in association with constrictive pericarditis.

Although acute pericarditis is a common and usual benign disorder, sometimes evolution to constrictive pericarditis may occur. We present a case of constrictive pericarditis late after coronary bypass grafting, complicated by right sided heart failure. Edema formation was aggravated due to protein-losing enteropathy, resulting in hypoalbuminemia. Imaging of constrictive pericarditis was done by ultrasound as well as simultaneous pressure recording of the right and left ventricle. Imaging of intestinal protein loss was possible using intravenous Technetium-99m-labelled human serum albumin.