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R Vanholder

Publications and source records attributed to R Vanholder.

At least 55 records · Page 3Linked to original sources

Uremic toxins and peritoneal dialysis.

Uremic toxicity is related in part to the accumulation of toxic substances, the nature of which has only partly been characterized. Because of the use of a highly permeable membrane and better preservation of the residual renal function, it could be anticipated that some of these uremic toxins are more efficiently cleared across the peritoneal membrane, and that the plasma and tissue levels of these compounds are lower than in hemodialysis patients. This article analyzes the generation and removal of several uremic toxins in peritoneal dialysis patients. The following uremic toxins are discussed: beta2-microglobulin, advanced glycation end products, advanced oxidation protein products, granulocyte inhibitory proteins, p-Cresol, and hyperhomocysteinemia. Some recent studies are reviewed suggesting that uremic toxins are involved in the progression of renal failure and are at least partially removed by peritoneal dialysis. We conclude that, although the plasma levels of some of these compounds are lower in peritoneal dialysis versus hemodialysis patients, it does not mean that the peritoneal dialysis patient is "better" protected against the numerous disturbances caused by these toxins.

Animals↗

The anti-proliferative effect of calcitriol on HL-60 cells is neutralized by uraemic biological fluids.

BACKGROUND: It has been demonstrated that uraemic serum/ultrafiltrate inhibits cell-mediated immune response in vitro, and that it suppresses calcitriol synthesis and its biological actions. METHODS: In the present in vitro study, the effect of calcitriol, uraemic ultrafiltrate (UUF) and a combination of both on the human promyelocytic leukaemia cell line, HL-60, was studied by evaluating bromodeoxyuridine (BrdU) incorporation into the DNA, luminol-amplified chemiluminescence (CL) production, expression of CD14, and levels of vitamin D receptor mRNA (VDR mRNA) and CD14 mRNA. RESULTS: The ability of calcitriol to block cell proliferation (37.4+/-5.4 to 30.5+/-5.6% cells incorporating BrdU, P:<0.01) was neutralized when UUF was applied together with calcitriol (53.4+/-21.3% cells incorporating BrdU, P:<0.01 vs calcitriol alone). Similarly to what was observed for BrdU incorporation, the CL production of HL-60 cells was enhanced in the presence of calcitriol (20126+/-10154 to 61528+/-24021 cpm, P:<0.01), and was suppressed again in the presence of calcitriol and UUF (20916+/-12075 cpm, P:<0.01 vs calcitriol alone); finally UUF also inhibited the calcitriol-induced CD14 expression (71.1+/-11.2 to 54.9+/-17.7% CD14 positive cells, P:<0.05). On the other hand, the calcitriol-induced CD14 mRNA levels were not significantly different in the presence of calcitriol and UUF compared to calcitriol alone. This points to an inhibition by UUF at a post-transcriptional level. Similar data were found for VDR mRNA levels. UUF was fractionated by HPLC in four fractions, hydrophilic uraemic solutes being eluted first (F1) and hydrophobic solutes being eluted last (F4); fractions 1, 2 and 3 simultaneously affected both BrdU incorporation and CL production in a significant way. CONCLUSIONS: It is concluded that UUF contains factors that impair calcitriol-activated function of HL-60 cells. Hence, the differentiation and immune response of these promyelocytic leukaemia cells, as induced by the supplementation of calcitriol, is neutralized in the presence of uraemic biological fluids. This may be of relevance for the propensity to infection and malignancy of the uraemic patient.

Biological Factors↗

Relationship between gastric emptying and clinical and biochemical factors in chronic haemodialysis patients.

BACKGROUND: Gastroparesis is an important side-effect of end-stage renal disease because of its influence on nutritional status. METHODS: In this study, 56 equilibrated haemodialysis patients were evaluated by radioisotopic examination for gastric emptying time. These data were correlated to anthropometrical as well as biochemical parameters. RESULTS: The half-life time for gastric emptying was 83+/-34 min in the overall population, compared to 50+/-15 min in a normal reference population. Prealbumin, mean fibular nerve-conduction velocity and intra- as well as extracorpuscular folic acid were significantly different between patients with the lowest and highest gastric emptying times. Linear correlation analysis between the half-life for residual radioactivity and the remaining parameters yielded a significant correlation for blood urea nitrogen, serum folic acid, intracorpuscular folic acid, serum vitamin B(12), serum C-reactive protein, serum prealbumin and mean fibular nerve-conduction velocity. CONCLUSIONS: This study demonstrates that gastric emptying is significantly delayed in end-stage renal disease patients. The delay is associated with changes in biochemical indicators of nutritional status such as serum albumin and prealbumin.

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Journal Article↗

Pathophysiologic features and prevention of human and experimental acute tubular necrosis.

Acute renal failure (ARF) remains a common and potentially devastating disorder that affects as many as 5% of all hospitalized patients, with a higher prevalence in patients in critical care units. The focus of this article is on categorizing recent pathophysiologic and clinically relevant developments in the field. The vascular and tubular factors in the pathogenesis of ARF, together with the potential mechanisms of recovery and repair of the injured kidney, are discussed. A number of experimental and clinical interventions to prevent. ARF are summarized. Although the clinical treatment of these patients is still largely supportive and many recent clinical trials showed rather negative results, it is hoped that basic research will provide therapeutic tools to improve the grim prognosis of this disease in the future.

Animals↗

What is the renal replacement method of first choice for intensive care patients?

Renal replacement therapy for the patient with acute renal failure on the intensive care unit can be offered in several different formats: intermittent hemodialysis (IHD), continuous renal replacement therapy (CRRT), and slow low-efficient daily dialysis (SLEDD). It is frequently claimed that CRRT offers several advantages over IHD, but most of these, such as correction of metabolic acidosis, better recovery of renal function, better clinical outcome due to application of biocompatible dialysis membranes, correction of malnutrition, and better removal of cytokines, are not corroborated by the results of controlled prospective studies. There is also no evidence that CRRT results in a better survival, compared with IHD. The only potential advantages of CRRT that stood the test of clinical evaluation (hemodynamic stability, correction of hypervolemia, better solute removal) can be offered as well by SLEDD. In addition, the latter strategy is less expensive because the same infrastructure is used as for IHD, while the patient is not immobilized continuously, which leaves time free for other activities such as nursing care and technical investigations. SLEDD is a relatively young technique, so thorough clinical studies are lacking. Nevertheless, the hypothesis is proposed that SLEDD offers a valuable alternative to the classical dialysis strategies, applied in the intensive care patient.

Acute Kidney Injury↗

Mimicry of surreptitious diuretic ingestion and the ability to make a genetic diagnosis.

Gitelman's syndrome, also known as "hypocalciuric variant of Bartter's syndrome", is a cause of chronic hypokalemia and hypomagnesemia in adults. A specific gene has been found responsible for this disorder, encoding the thiazide-sensitive NaCl coporter (TSC) in the distal convoluted tubule. We describe a psychiatric patient with chronic symptomatic hypokalemia and hypomagnesemia whose electrolyte disturbances were subsequently misdiagnosed as an acute alcohol and benzodiazepine withdrawal syndrome, as chronic diuretic abuse and as a classical Bartter's syndrome. Finally, genetic investigation revealed the presence of mutations in the SLC12A3 gene leading to the proper diagnosis of Gitelman's syndrome. We emphasize that Gitelman's syndrome should be suspected in every hypokalemic patient with biochemical resemblance of diuretic ingestion, especially when repeated toxic screens for diuretics are negative. The ability to make a molecular-genetic diagnosis can be of practical benefit in confusing clinical settings.

Adult↗

Heparin-induced release of protein-bound solutes during hemodialysis is an in vitro artifact.

BACKGROUND: Several studies have pointed to a release of drugs or protein-bound solutes from their binding sites during heparinization. The effect is attributed to the metabolism of triglycerides to free fatty acids (FFAs), which compete with drugs for protein binding sites. This study evaluated the impact of intradialytic heparin on the free concentration of the uremic toxin p-cresol and on FFAS: METHODS: Blood samples from hemodialysis (HD) patients, before and during HD, were collected with selected anticoagulation strategies. We assessed the effects of standing time, temperature, pH, and the addition of a lipase inhibitor, tetrahydrolipstatin (THL) to blood samples on the free p-cresol concentration. p-Cresol was analyzed by HPLC with fluorescence detection. We measured FFAs by gas chromatography, and the free fractions of added valproic acid and phenytoin were evaluated by fluorescence polarization immunoassay. RESULTS: In blood samples (n = 22) not submitted to a specific treatment, free p-cresol increased from 9.9 +/- 5.1 to 31.9 +/- 22.3 micromol/L after 30 min of heparin HD (P < 0.001) and correlated significantly with FFAs (r = 0.80; P = 0.002; n = 12). There was no increase in free p-cresol during heparin-free HD (n = 6) and trisodium citrate HD (n = 9). In addition, p-cresol in ultrafiltrates (n = 3) did not correspond to the free p-cresol in heparinized blood, suggesting that the increase in free p-cresol was artifactual. The release of p-cresol in the test tube was enhanced by standing time (n = 6), sample temperature (n = 6), and alkaline pH (n = 6). Inhibition of lipase activity with THL prevented the increase of FFAs (n = 6) and the release of free p-cresol during HD (n = 22). These results were corroborated by the study of the free fraction of valproic acid (n = 6) and phenytoin (n = 6). CONCLUSIONS: The free concentrations of protein-bound solutes in plasma of heparinized patients are influenced by external factors that alter the lipase activity in the test tube. The free fraction does not increase during HD when lipase activity is neutralized at the time of blood sampling, so that previously reported increases are probably artifacts.

Aged↗

Advanced glycation end products: specific fluorescence changes of pentosidine-like compounds during short daily hemodialysis.

BACKGROUND: Advanced glycation end products (AGE) accumulate in uremia and represent an important etiopathogenetic cause of morbidity in dialyzed patients. Conventional hemodialysis treatment seems to be ineffective in lowering AGE levels. We wished to investigate whether daily hemodialysis (DHD), a treatment that seems to result in better clinical condition in end-stage renal disease patients, is effective in the reduction of these compounds. METHODS: We evaluated 10 non-diabetic patients on standard hemodialysis (SHD = 3 x 4 h/week) for more than 6 months by a crossover study. These patients were assigned randomly to 6 months of DHD (6 x 2 h/week) or 6 months of SHD. Then, they were switched to 6 months of the alternative treatment. At the end of these two periods, we studied pentosidine-like AGE compounds by measuring the total fluorescence at a wavelength characteristic for these substances: Ex: 335nm/Em:385nm; we also measured protein-linked pentosidine at the same time points. Finally, we determined the AGE-related total fluorescence in the deproteinized serum of 13 uremic patients on peritoneal dialysis (CAPD) and of 10 healthy controls. RESULTS: Pre-HD AGE-related total fluorescence obtained after 6 months of DHD was significantly lower than that obtained with standard HD (DHD = 201.3 +/- 36.4 AU/ml vs. SHD = 267.5 +/- 141.4 AU/ml, p = 0.03). The extraction rate per minute of dialysis was slightly, but not significantly higher during DHD than SHD (0.29 +/- 0.11% vs. 0.23 +/- 0.04, p = 0.07). AGE-related total fluorescence pre-HD values in patients treated by SHD and DHD were about 20-fold higher than in control subjects. They did not differ from CAPD patients. The pre-dialysis level of protein-linked pentosidine was significantly lower in DHD than in SHD (DHD = 16.12 +/- 4.71 pmol/mg protein, SHD = 22.64 +/- 6.86 pmol/mg protein, p < 0.01). CONCLUSIONS: DHD showed a reduction in AGE-related total fluorescence, although the mean value remained higher than in control subjects. DHD is also accompanied by a decrease in protein-linked pentosidine.

Arginine↗

Dyspepsia and gastric emptying in chronic renal failure patients.

AIMS: Chronic renal failure (CRF) patients frequently suffer from dyspeptic complaints such as nausea, vomiting, abdominal distension, early satiety and anorexia. The aim of the present study was to define the prevalence of dyspeptic complaints and delayed gastric emptying in CRF patients. MATERIAL AND METHODS: Dyspeptic complaints were assessed anamnestically in 62 non-dialyzed CRF patients. Gastric emptying for solids was evaluated by the 13C-octanoic acid breath test in the same population. The CRF patients were compared to 27 healthy volunteers. RESULTS: There was a high prevalence (48%) of dysmotility-like dyspepsia in the investigated population. The gastric emptying rates of CRF patients and healthy volunteers were significantly different (median gastric emptying t(1/2) 83 min versus 60 min, p < 0.01). Diabetic CRF patients had lower gastric emptying rates than non-diabetic CRF patients (median gastric emptying time t(1/2) 113 min versus 77 min, p < 0.01). Even the non-diabetic CRF patients had a significantly delayed gastric emptying rate compared to the healthy volunteers (77 min versus 60 min, p < 0.05). CONCLUSION: It is concluded that dysmotility-like dyspeptic complaints and delayed gastric emptying are highly prevalent in CRF patients.

Adolescent↗

Uremic toxicity: present state of the art.

The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest.

Cardiovascular Diseases↗

Peritoneal dialysis favorably influences early graft function after renal transplantation compared to hemodialysis.

BACKGROUND: Delayed graft function (DGF) and acute renal failure (ARF) after renal transplantation negatively influence short- and long-term graft outcome. Peritoneal dialysis as pretransplantation dialysis modality was reported to influence favorably the recovery of renal function immediately after kidney transplantation. It has been hypothesized that fluid status was the factor explaining this better outcome. This hypothesis was tested in this study by multivariate analysis, also including other factors related to DGF and ARF. METHODS: The records of peritoneal dialysis (PD; n=40) and hemodialysis (HD; n=79) patients receiving a first cadaveric kidney transplantation at the University Hospital Gent were analyzed. RESULTS: DGF and ARF were observed in 33 (27 HD and 6 PD, P=0.03) and 14 (14 HD and 0 PD, P=0.01) patients, respectively. The number of days needed to reach a serum creatinine 50% below that before transplantation (T1/2(SCr)), was correlated with cold ischemia time (CIT) (P<0.001) and body weight gain (BWG) (P<0.01) and was inversely correlated with urinary output in the first 24 hr (P<0.001), fluid load (P<0.001), and central venous pressure (P<0.001). A multivariate model with CIT (P<0.001), PD as pretransplantation dialysis mode (P=0.01), urinary output in the first 24 hr (P=0.001), BWG (P=0.05), and fluid load (P=0.01) resulted in an R2 of 0.32 (P<0.001). Using Cox regression analysis, the relative risk for a prolonged T1/2(SCr) increased with 4%/hr CIT (P=0.01) and with 1%/kg BWG (P=0.02). Fluid load decreased the relative risk with 5%/liter (P<0.001) and PD as pretransplantation modality favorably modified the relative risk by a factor of 1.6 (P=0.01). CONCLUSION: PD as pretransplantation dialysis modality can reduce the incidence and the severity of delayed recovery of renal function after renal transplantation. This protective effect was independent from CIT, and fluid status, two other major influencing factors.

Acute Kidney Injury↗

Effect of radiographic contrast agents on leukocyte metabolic response.

BACKGROUND: The use of radiographic contrast media in the setting of possible bowel ischemia and potential perforation is known to carry a risk of morbidity and mortality. However, studies of the effect of available contrast media on host immunological defense mechanisms are lacking. We have examined the effect of barium and of two water-soluble contrast agents of differing iodine concentration and osmolality, Conray 30 and Cysto Conray II, on leukocyte phagocytosis. MATERIALS AND METHODS: Blood samples were incubated with the contrast media alone (termed the "resting state"), and in combination with a standard phagocytic challenge (Zymosan polysaccharide extract) and with Staphylococcus epidermidis, Streptococcus faecalis and Escherichia coli, to determine the effect of contrast media upon leukocyte phagocytic response. Incubation with saline was used as control. In the case of barium, the "resting state" and standard challenge experiments were repeated at nine dilutions, ranging from 1:1 to 1:1000. The leukocyte phagocytic response was measured in two ways: CO2 generation (an index of metabolic activity) and chemiluminescence (an index of generation of reactive oxygen species and bacterial killing). RESULTS: Barium, at clinical dilutions, causes a significant increase of baseline "resting state" phagocytic activity, which in turn leads to significant blunting of subsequent response to phagocytic challenge and adversely affects the response to all bacteria tested. There is no baseline activation of leukocytes by the water-soluble media, although there was some inhibition (rather than activation) of leukocyte metabolic activity. The effect of the water-soluble media on bacteria was more complex (although inhibition is minor compared to barium). CONCLUSIONS: Our data demonstrate that barium is a significant activator of phagocytic cells, which results in deactivation of phagocytic response when challenged; these data serve to explain the enhanced adverse effect of barium in cases of fecal peritonitis.

Barium Sulfate↗

Experimental study of mortality and morbidity of contrast media and standardized fecal dose in the peritoneal cavity.

BACKGROUND: The use of radiographic contrast media in the setting of possible bowel ischemia and potential perforation is known to be associated with increased clinical risk. However, there is a lack of controlled studies using a standard native fecal load to define and compare the intrinsic mortality and morbidity among options of contrast media currently available to the radiologist. We have compared the mortality and gross and histopathologic morbidity of a standard intraperitoneal native fecal dose in the guinea pig, using barium, two iodinated media, saline and air. MATERIALS AND METHODS: The study was performed on adult Hartley guinea pigs. A standard native fecal solution with a colony count of 10(8) aerobes and 2 x 10(7) anaerobes was prepared, and the LD50 of intraperitoneal injection of the solution was determined. The standard solution at the LD50 dose was then used to compare the mortality and morbidity when commercial barium sulfate (18% w/v), Conray 30 (iothalamate meglumine 30%), 1:1 dilution of Conray 30 with sterile water, termed Conray "15" (iothalamate meglumine 15%), saline and air, were added to the intraperitoneal injection of the fecal solution in five groups of 20 animals each. Mortality and acute (96 h) and chronic (30 days) gross and histopathology were assessed and graded according to a standard system and analyzed statistically. RESULTS: Barium was significantly more deleterious than the dilute water-soluble iodinated media, saline and air. Mortality occurred within 24 h in the barium group and within the initial 48 h in all groups as follows: barium 19/20 (95%); Conray 30 16/20 (80%); Conray "15" 7/20 (35%); saline 0; air 0. Acute gross and histopathology showed extensive grade 4 lesions in 19/19 barium animals; less severe lesions were present in a lesser percentage of the animals in the other four groups. Entirely chronic lesions were present only in the single surviving barium animal and were non-significant (< 400 microns) or absent in the other four groups. CONCLUSIONS: In our study, barium incurred the most significant deleterious short and long-term effects in the setting of fecal peritonitis. Dilute water-soluble media offer a much greater margin of safety. Saline under sonographic guidance is less deleterious than any of the positive radiographic contrast media. However, in our study, air was the safest contrast medium in the setting of peritoneal soiling.

Animals↗