Watske Smit

Growth factors VEGF and TGF-β1 in peritoneal dialysis ☆ ☆☆ ★ ★★

The morphologic alterations in the kidney and the retina that can be present in patients with diabetic microangiopathy are mediated by growth factors. Vascular endothelial growth factor (VEGF) is a mediator of neoangiogenesis in diabetic retinopathy. Transforming growth factor-β (TGF-β) is involved in the extracellular matrix proliferation in diabetic nephropathy. The aim of the present study was to investigate the presence of VEGF and TGF-β1 in peritoneal effluents of patients undergoing continuous ambulatory peritoneal dialysis who are being treated with glucose-containing dialysis solutions in relation to parameters of peritoneal transport. Standard peritoneal permeability analyses with 3.86% glucose dialysate were performed in 16 stable patients undergoing peritoneal dialysis (PD) (median duration of PD 39 months, range 1 to 104 months). The power relationship that is present between dialysate/serum (D/S) ratios of serum proteins that are transported only across the peritoneal membrane and their molecular weights was used to predict the D/S ratios when diffusion would be the only explanation for the measured dialysate concentration. It was assumed that all TGF-β1 in the circulation was bound to α2-macroglobulin. The D/S ratios of VEGF (P < .0005) and TGF-β1 (P < .015) were significantly higher than expected when VEGF and TGF-β1 would have been transported from the circulation only by diffusion. No relationship was present between the effluent concentration attributed to the local production of VEGF (LVEGF) and that of TGF-β1 (LTGF-β1). LVEGF correlated with the mass transfer area coefficient (MTAC) creatinine value (r = 0.69, P < .007), MTAC urate value (r = 0.60, P < .02), and glucose absorption value (r = 0.75, P < .004), all reflections of the peritoneal vascular surface area. A negative correlation was observed between the transcapillary ultrafiltration (926 mL/4 h, 394 to 1262 mL/4 h) and LVEGF (r = –0.52, P < .045). This negative tendency was also observed between the net ultrafiltration (622 mL/4 h, –43 to 938 mL/4 h) and LVEGF (r = –0.48) but did not reach significance. LVEGF and the duration of treatment did not correlate, possibly because of the relatively small number of patients. LTGF-β1 showed no relationship with transport parameters or duration of treatment. In conclusion, we found evidence for the local production of both VEGF and TGF-β1 in the peritoneal membrane of patients undergoing long-term peritoneal dialysis with glucose-based dialysate solutions. The analogy with VEGF in diabetic retinopathy suggests a pathogenetic role of high dialysate glucose concentrations in the development of these alterations in the peritoneal membrane. (J Lab Clin Med 1999;134:124-32)

Bench-to-bedside review: Preventive measures for contrast-induced nephropathy in critically ill patients

An increasing number of diagnostic imaging procedures requires the use of intravenous radiographic contrast agents, which has led to a parallel increase in the incidence of contrast-induced nephropathy. Risk factors for development of contrast-induced nephropathy include pre-existing renal dysfunction (especially diabetic nephropathy and multiple myeloma-associated nephropathy), dehydration, congestive heart failure and use of concurrent nephrotoxic medication (including aminoglycosides and amphotericin B). Because contrast-induced nephropathy accounts for a significant increase in hospital-acquired renal failure, several strategies to prevent contrast-induced nephropathy are currently advocated, including use of alternative imaging techniques (for which contrast media are not needed), use of (the lowest possible amount of) iso-osmolar or low-osmolar contrast agents (instead of high-osmolar contrast agents), hyperhydration and forced diuresis. Administration of N-acetylcysteine, theophylline, or fenoldopam, sodium bicarbonate infusion, and periprocedural haemofiltration/haemodialysis have been investigated as preventive measures in recent years. This review addresses the literature on these newer strategies. Since only one (nonrandomized) study has been performed in intensive care unit patients, at present it is difficult to draw firm conclusions about preventive measures for contrast-induced nephropathy in the critically ill. Further studies are needed to determine the true role of these preventive measures in this group of patients who are at risk for contrast-induced nephropathy. Based on the available evidence, we advise administration of N-acetylcysteine, preferentially orally, or theophylline intravenously, next to hydration with bicarbonate solutions.

Peritoneal function in clinical practice: the importance of follow-up and its measurement in patients. Recommendations for patient information and measurement of peritoneal function.

A review is given on peritoneal function, especially ultrafiltration and ultrafiltration failure followed by recommendations on how to translate pathophysiology into clinical practice. The subsequent consequences for management of peritoneal membrane function and for patient information are also included.

Peritoneal Membrane Failure in Peritoneal Dialysis Patients

A review is given of the conditions associated with peritoneal membrane failure, and the possible causes. Ultrafiltration failure is the most important manifestation. It is mostly associated with high transport rates of low molecular weight solutes suggesting the presence of a large vascular surface area. Enlargement of the peritoneal surface area can be functional (effective surface area: more perfused microvessels) or anatomic (more microvessels). The former is likely to be present in some patients in the beginning of peritoneal dialysis, and also during peritonitis. The latter can develop in long-term peritoneal dialysis.

Biological markers in the peritoneal dialysate effluent: are they useful.

A review is given on biomarkers in peritoneal effluent. It comprises methods to distinguish between diffusion and local production. This is followed by examples of various biomarkers. Their potential use is discussed in 4 situations: inherent fast transporters, longitudinal follow-up of patients, biocompatibility testing of new dialysis solutions, and their potential use in the detection of patients who are likely to develop encapsulating peritoneal sclerosis.

Variability of effluent cancer antigen 125 and interleukin-6 determination in peritoneal dialysis patients

BACKGROUND Cancer antigen (CA) 125 is a glycoprotein that provides data on the state of the peritoneal membrane in peritoneal dialysis (PD). Interleukin-6 (IL-6) acts as a mediator in acute-phase responses. The study evaluated the usefulness of CA125 and IL-6 in random effluent samples, by assessing their variability in individual patients during clinical practice at the outpatient department. METHODS This longitudinal prospective study was conducted from 2007 till 2009. Participants included 52 stable PD patients aged ≥ 18 years. Effluent samples were obtained during regular outpatient visits and appearance rates (ARs) were calculated. Inter- and intra-individual variability was determined by the coefficient of variation (CV). A linear mixed model was used to analyse time courses. Furthermore, release patterns of these effluent markers were studied. RESULTS CA125-AR of short-term patients (≤ 24 months) ranged from 39.2 to 766.7 U/min and IL-6-AR from 15.5 to 220.0 pg/min. Long-term patients (≥ 25 months) had a CA125-AR of 7.3-1534.0 U/min and IL-6-AR of 6.9-956.4 pg/min. Overall, CV(intra) was 15% in effluent CA125-AR and 28% in IL-6-AR. Intermediate sampling during a 4-h dwell showed a linear increase of CA125 and IL-6 effluent concentrations. The trend of CA125-AR was different (P = 0.001) between short- and long-term patients. A negative relationship was found between CA125 (r = -0.44, P = 0.02) and PD duration. CONCLUSIONS The clinical relevance of effluent CA125 determinations from an unstandardized dwell during every outpatient visit is reasonable, as judged from the CV(intra). The inferior CV(intra) values of ARs as compared to effluent values indicate that ARs should only be calculated under standardized conditions. A single IL-6 measurement, as a predictor of outcome, should be interpreted cautiously.

N-acetylcysteine and other preventive measures for contrast-induced nephropathy in the intensive care unit

The increase in diagnostic imaging procedures that require infusion of intravenous radiographic contrast has led to a parallel increase in the incidence of contrast-induced nephropathy (CIN). Since CIN accounts for a significant increase of hospital-acquired renal failure, length of stay and mortality, several additive strategies to prevent CIN are presently advocated, including N-acetylcysteine (NAC), sodium bicarbonate, theophylline or fenoldopam, and peri-procedural hemofiltration/hemodialysis. As only one (non-randomized) study has been performed in the intensive care setting, at present it is hard to give firm recommendations on preventive measures for CIN in intensive care patients. Indeed, future studies are needed to determine the true role of the above-mentioned preventive measures in critically ill patients at risk for CIN. Since NAC has only few side-effects, we presently advise NAC as an additive preventive measure in the intensive care setting. Theophylline or sodium bicarbonate hydration are viable options, either in conjunction NAC or as alternatives.

Fluid transport with time on peritoneal dialysis: the contribution of free water transport and solute coupled water transport.

Ultrafiltration in peritoneal dialysis occurs through endothelial water channels (free water transport) and together with solutes across small pores: solute coupled water transport. A review is given of cross-sectional studies and on the results of longitudinal follow-up.

Dry body weight and ultrafiltration targets in peritoneal dialysis.

A review is given on methods that can be used for the assessment of dry body weight in peritoneal dialysis patients. Besides clinical examination, the use of natriuretic hormone concentrations in plasma, and the value of multifrequency bio-impedance analysis is discussed. Ultrafiltration targets as formulated in various guidelines are reviewed. Finally, it is concluded that the ultrafiltration target is the amount required to keep patients euvolemic with an exposure to glucose that is as low as possible.

Future technologies and techniques in peritoneal dialysis—opportunities and challenges ahead

In the last 5 years, we have started to witness the emergence of new technologies and techniques that offer the potential for improved patient outcomes but which often still lack clinical demonstration and/or confirmation in well-designed, multicentre studies. These include biocompatible solutions, glucose sparing regimens, low-sodium solutions, bimodal solution formulations and continuous flow peritoneal dialysis (CFPD). This review discusses the potential benefits ascribable to each of these technologies and an analysis of the challenges that have to be surmounted before anyone of these candidate technologies can be declared as established. The demonstration of either hard clinical endpoints or validated surrogate endpoints is very feasible in terms of sample size requirements for some outcome measures, such as preservation of RRF, but will be much more challenging for other endpoints such as preservation of UF capacity.