Machteld M. Zweers

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)

INDUCTION OF CHRONIC KIDNEY FAILURE IN A LONG-TERM PERITONEAL EXPOSURE MODEL IN THE RAT: EFFECTS ON FUNCTIONAL AND STRUCTURAL PERITONEAL ALTERATIONS

♦ Background: A long-term peritoneal exposure model has been developed in Wistar rats. Chronic daily exposure to 3.86% glucose based, lactate buffered, conventional dialysis solutions is possible for up to 20 weeks and induces morphological abnormalities similar to those in long-term peritoneal dialysis (PD) patients. The possible effects of kidney failure in this model are unknown. The aim was to analyze the effects of chronic kidney failure on peritoneal function and morphology, alone and in combination with PD exposure, in a well-established, long term, peritoneal exposure model in the rat. ♦ Methods: 40 male Wistar rats were randomly assigned into four experimental groups: no nephrectomy, no peritoneal exposure (sham; n = 8); nephrectomy, no peritoneal exposure (Nx; n = 12); no nephrectomy, with peritoneal exposure (PD; n = 8); and nephrectomy, with peritoneal exposure (NxPD; n = 12). The nephrectomy consisted of a one-step 70% nephrectomy. The peritoneal exposure groups were infused once daily for 16 weeks with a 3.86% glucose-based dialysis solution. Development of chronic kidney disease was monitored during the experiment. Peritoneal function and morphological assessment of the peritoneal membrane were performed at the end of the experiment. ♦ Results: During follow-up the nephrectomized groups developed uremia with remarkable renal tubular dilatation and glomerular sclerosis in the renal morphology. Functionally, uremia (Nx) and PD exposure (PD) alone showed faster small solute transport and a decreased ultrafiltration capacity, which were most pronounced in the combination group (NxPD). The presence of uremia resulted in histological alterations but the most severe fibrous depositions and highest vessel counts were present in the PD exposure groups (PD and NxPD). Significant relationships were found between the number of vessels and functional parameters of the peritoneal vascular surface area. ♦ Conclusion: It is possible to induce chronic kidney failure in our existing long-term peritoneal infusion model in the rat. The degree of impairment of kidney function after 16 weeks is comparable to chronic kidney disease stage IV. Uremia per se induces both functional and morphological alterations of the peritoneal membrane. An additive effect of these alterations is present with the addition of chronic kidney failure to the model. The latter makes the present long-term model important in better understanding the pathophysiology of the peritoneal membrane in PD.

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.

The effects of a dialysis solution with a combination of glycerol/amino acids/dextrose on the peritoneal membrane in chronic renal failure.

♦ Background: Long-term peritoneal dialysis (PD) with conventional glucose based, lactate-buffered PD fluids may lead to morphological and functional alterations of the peritoneal membrane. It was hypothesized that long-term exposure to a different buffer and a mixture of osmotic agents would cause less peritoneal abnormality. ♦ Objectives: To investigate the effects of long-term exposure to a bicarbonate/lactate-buffered dialysis solution with a mixture of osmotic agents: glycerol 1.4%, amino acids 0.5%, and dextrose 1.1% (= 1% glucose) (GLAD) in a rat model with chronic kidney failure. ♦ Methods: All rats underwent a peritoneal catheter implantation and a 70% nephrectomy. Thereafter, the rats were randomly divided into 3 groups: GLAD, 3.86% Dianeal (Baxter, Nivelles, Belgium), and buffer (Physioneal without glucose, Baxter). All rats were infused daily for 16 weeks with the appropriate PD fluid. Afterwards, a peritoneal permeability analysis (SPARa) was performed using 3.86% Physioneal in all groups. After the SPARa, the rats were sacrificed to obtain tissue samples for morphometric determinations. Omental tissue was stained with picro Sirius red for assessment of fibrosis and with CD31 for vessel density. ♦ Results: GLAD and Dianeal showed faster small solute transport compared to the hypotonic buffer. No differences between the groups were present in ultrafiltration. Dianeal had the lowest value for free water transport and the highest protein clearances. Total triglyceride in plasma was not different between GLAD and the buffer. Vessel density after GLAD exposure (20 V/F) was very similar to the value found for the buffer solution (17 V/F); Dianeal caused a significantly higher value (35 V/F, p < 0.01). Also, the amount of fibrosis was higher in the Dianeal-exposed rats (p < 0.01). ♦ Conclusion: Both hypertonic dialysis solutions increased peritoneal solute transport. GLAD exposure was associated with the best preservation of peritoneal morphology. The results of GLAD were very similar to those of the bicarbonate/lactate-buffered solution without osmotic agents. Studies in humans are needed for further assessment of GLAD.

Effects of reducing the lactate and glucose content of PD solutions on the peritoneum. Is the future GLAD

Background. Long-term peritoneal dialysis (PD) may lead to functional and morphologic changes in the peritoneal membrane, probably because of the continuous exposure to conventional dialysis solutions. Methods. The morphologic changes include neoangiogenesis and fibrosis. The authors of this article developed a long-term peritoneal exposure model in rats, in which the morphological alterations could be induced after daily peritoneal infusion of a 3.86% glucose/lactate-buffered conventional PD solution. Results and Conclusions. In the present article, a review of the model and of the results obtained with various available and experimental solutions is given. It appeared that high lactate concentrations contributed to the glucose-induced neoangiogenesis by pseudohypoxia. Glucose degradation products were probably more important in the induction of peritoneal fibrosis. The promising results of a combination of amino acids, glycerol and glucose, each in a low concentration, buffered with either pyruvate or bicarbonate/lactate, are presented and discussed. The combination of glycerol, amino acids and dextrose, dissolved in a bicarbonate/lactate buffer (GLAD), may be an option for a new generation of dialysis fluids.

The relationship between effluent potassium due to cellular release, free water transport and CA125 in peritoneal dialysis patients.

Background. Recently, we found evidence of effluent potassium (K+) additional to diffusion and convection, suggesting cellular release (CR). Its relationship with free water transport (FWT) in stable peritoneal dialysis (PD) patients suggested an effect of hypertonicity of the dialysis solution leading to cell shrinkage. The aim of the present study was to reproduce these findings in groups according to PD duration and to further investigate the role of mesothelial cells in the observed phenomenon. Methods. Standard peritoneal permeability analyses done with 3.86% glucose were analysed cross-sectionally in three different groups: short-term (n = 53) 0–2 years PD treatment; medium-term (n = 24) 2–4 years PD and long-term (n = 26) > 4 years PD. Results. The time courses for FWT and cellular release of K+ (CR-K+) during the dwell were not significantly different among the groups. Cancer antigen (CA) 125 was highest in the short-term group (P ≤ 0.02) and had a strong positive correlation with mass transfer area coefficient of creatinine (MTAC-creatinine) only in the short-term group (r = 0.62, P ≤ 0.01). CA125 had no relationship with either CR-K+ or FWT, except for negative relationships in the short-term group (CR-K+, r = −0.41, P ≤ 0.05; FWT, r = −0.54, P ≤ 0.05). Conclusion. We conclude that the correlation of CA125 and MTAC-creatinine is dependent on PD duration and underlines the in vitro observation that mesothelial cells produce vasoactive substances that may increase the peritoneal surface area. However, CA125 is not directly related to CR-K+ or FWT. Therefore, the relationship between FWT and CR-K+ is likely to reflect hypertonic cell shrinkage, regardless of the duration of PD, and confirms our earlier findings.