[show abstract][hide abstract] ABSTRACT: Mesothelial-to-mesenchymal transition (MMT) is an auto-regulated physiological process of tissue repair that in uncontrolled conditions such as peritoneal dialysis (PD) can lead to peritoneal fibrosis. The maximum expression of peritoneal fibrosis induced by PD fluids and other peritoneal processes is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. Tamoxifen, a synthetic estrogen, has successfully been used to treat retroperitoneal fibrosis and EPS associated with PD. Hence, we used in vitro and animal model approaches to evaluate the efficacy of Tamoxifen to inhibit the MMT as a trigger of peritoneal fibrosis. In vitro studies were carried out using omentum-derived mesothelial cells (MCs) and effluent-derived MCs. Tamoxifen blocked the MMT induced by transforming growth factor (TGF)-β1, as it preserved the expression of E-cadherin and reduced the expression of mesenchymal-associated molecules such as snail, fibronectin, collagen-I, α-smooth muscle actin, and matrix metalloproteinse-2. Tamoxifen-treatment preserved the fibrinolytic capacity of MCs treated with TGF-β1 and decreased their migration capacity. Tamoxifen did not reverse the MMT of non-epitheliod MCs from effluents, but it reduced the expression of some mesenchymal molecules. In mice PD model, we demonstrated that MMT progressed in parallel with peritoneal membrane thickness. In addition, we observed that Tamoxifen significantly reduced peritoneal thickness, angiogenesis, invasion of the compact zone by mesenchymal MCs and improved peritoneal function. Tamoxifen also reduced the effluent levels of vascular endothelial growth factor and leptin. These results demonstrate that Tamoxifen is a therapeutic option to treat peritoneal fibrosis, and that its protective effect is mediated via modulation of the MMT process.
PLoS ONE 01/2013; 8(4):e61165. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective: The aim of this study was to analyze the prevalence, clinical significance and prognostic implications of alterations in thyroid function tests (TFTs) in patients with acute kidney injury (AKI). Methods: A prospective study was carried out in patients hospitalized for AKI for 2 consecutive years. TFTs (serum thyrotropin [TSH], free thyroxine [FT4] and total triiodothyronine [T3] concentrations) were completed for each patient on 3 occasions: at admission, at hospital discharge and at their first outpatient visit. TFTs were related to clinical and analytical data. Thirty-five patients (16 women [45.7%], mean age ± SD, 65.2 ± 18.0 years) with AKI (creatinine 5.6 ± 2.2 mg/dL) were studied. There were 10 (28.6%), 10 (28.6%), 11 (31.4%) and 4 (11.4%) patients with prerenal, renal, mixed (prerenal and renal), and postrenal AKI, respectively. Results: Total prevalence of alterations in TFTs was 82.9% (n=29). Of those, euthyroid sick syndrome (ESS) with low T3 only was the most common (n=13, 37.1%) derangement. In the whole group of patients, median TSH (0.93 µU/mL, interquartile range 0.35-2.27 µU/mL)and mean FT4 (1.2 ± 0.3 ng/dL) were normal, whereas mean T3 was low (0.7 ± 0.1 ng/mL). TSH, FT4 and T3 were similar in different types of AKI. On simple regression analysis, we found a negative correlation only between TSH and serum urea concentrations (ro=-0.382; p=0.024). At hospital discharge (median hospital stay 6 days; range 2-10 days), TFT showed significant changes only in T3 concentrations (0.8 ± 0.3 ng/mL, p=0.013). At this point, the percentage of patients with normal TFT increased from 17.1% at baseline to 40% at discharge and then to 66.7% at their first outpatient visit. We found no association between the presence and type of alterations in TFT and clinical factors (sex, age, personal history of diabetes and/or hypertension, number and type of drugs used, number of signs and symptoms at AKI diagnosis, and degree, type and cause of AKI) or prognostic factors (hospital stay, recovery of renal function, need for renal replacement therapy by hemodialysis, development and degree of residual chronic renal failure and mortality) associated with AKI. Conclusion: Over 80% of AKI patients exhibit alterations in TFT. The commonest derangement is ESS (~70%), mainly low T3 syndrome, which is present in about one third of the patients with altered TFT. ESS recovers spontaneously as renal function improves. The presence of TFT alterations seems to not be associated with clinical and prognostic implications in AKI patients.
Journal of nephrology 03/2012; · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this research is to adapt a questionnaire designed for the assessment of needs and resources in patients with onco-haematological diseases – the CMAE-OH- to renal patients under dialysis treatment. We have conducted three different studies. The first one is an inter-judges study to determine the face validity of the tool. The second is a pilot study, to know how the designed tool works when used in renal patients under dialysis. The third study consists of the usage of the questionnaire in a biggest sample to determine the psychometric properties of the tool. After the adaptation of the tool we conclude that the questionnaire we have adapt it is useful to assess needs and resources in renal patients under dialysis, as well as CMAE-OH was when used with oncological patients. On the basis of our study, we reflexionate about the closeness between psychooncology and other subdisciplines in the area of health psychology like psychonephrology.
[show abstract][hide abstract] ABSTRACT: Depending on the cytokine microenvironment, macrophages (Mϕ) can adopt a proinflammatory (M1) or a profibrotic (M2) phenotype characterized by the expression of cell surface proteins such as CD206 and CD163 and soluble factors such as CC chemokine ligand 18 (CCL18). A key role for Mϕ in fibrosis has been observed in diverse organ settings. We studied the Mϕ population in a human model of peritoneal dialysis in which continuous stress due to dialysis fluids and recurrent peritonitis represent a risk for peritoneal membrane dysfunction reflected as ultrafiltration failure (UFF) and peritoneal fibrosis.
We used flow cytometry and quantitative reverse transcription-polymerase chain reaction to analyse the phenotype of peritoneal effluent Mϕ and tested their ability to stimulate the proliferation of human fibroblasts. Mϕ from non-infected patients were compared with those from patients with active peritonitis. Cytokine production was evaluated by enzyme-linked immunosorbent assay (ELISA) in spent dialysates and cell culture supernatants.
CD206(+) and CD163(+) M2 were found within peritoneal effluents by flow cytometry analysis, with increased frequencies of CD163(+) cells during peritonitis (P = 0.003). TGFB1, MMP9 and CCL18 messenger RNA (mRNA) levels in peritoneal macrophages (pMϕ) were similar to those found in M2 cells differentiated in vitro. The ability of pMϕ to stimulate fibroblast proliferation correlated with CCL18 mRNA levels (r = 0.924, P = 0.016). CCL18 production by pMϕ was confirmed by immunostaining of cytospin samples and ELISA. Moreover, CCL18 effluent concentrations correlated with decreased peritoneal function, which was evaluated as dialysate to plasma ratio of creatinine (r = 0.724, P < 0.0001), and were significantly higher in patients with UFF (P = 0.0025) and in those who later developed sclerosing peritonitis (P = 0.024).
M2 may participate in human peritoneal fibrosis through the stimulation of fibroblast cell growth and CCL18 production as high concentrations of CCL18 are associated with functional deficiency and fibrosis of the peritoneal membrane.
[show abstract][hide abstract] ABSTRACT: Background:
Transplantation has improved survival of end-stage renal disease patients. There are
more patients on waiting lists than there are available grafts. An increasing number of donors considered marginal are currently sources for transplantation.
A cold ischaemia time over 24h in marginal kidneys has a negative influence on immediate renal function and graft survival.
Our aim was to evaluate whether a decrease in cold ischaemia time influences the outcome in grafts from marginal donors.
Patients and Methods: We studied the patients transplanted in our centre from January 1st 2002 to December 31st 2005 who received a kidney from a deceased marginal donor.
Results: Cold ischaemia time over 18 hours has a significantly greater incidence of slow graft function (73.3% versus 65.8%) and delayed graft function (31.3% versus 18.9%). A trend was observed between the cold ischaemia time and the creatinine at five years (p=0.07). Neither the number of HLA mismatching, donor´s age or cause of
donor death were significantly related to slow graft function.
No relationship was observed between cold ischaemia time and the incidence of acute rejection or the serum creatinine values at 3, 6 and 12 months posttransplantation.
Efforts to shorten cold ischaemia time below an 18-hour limit have been rewarded with a
decrease in the incidence of slow graft function and beneficial effects on renal function.
Portuguese Journal of Nephrology and Hypertension. 01/2011; 25:37.
[show abstract][hide abstract] ABSTRACT: Peritoneal membrane deterioration during peritoneal dialysis (PD) is associated with epithelial-to-mesenchymal transition (EMT) of mesothelial cells (MC), which is believed to be mainly due to glucose degradation products (GDPs) present in PD solutions. Here we investigate the impact of GDPs in PD solutions on the EMT of MC in vitro and ex vivo.
For in vitro studies, omentum-derived MC were incubated with standard PD fluid or low-GDP solution diluted 1:1 with culture medium. For ex vivo studies, 33 patients, who were distributed at random to either the 'standard' or the 'low GDP' groups, were followed over 24 months. Effluents were collected every 6 months to determine EMT markers in effluent MC.
Exposure of MC to standard fluid in vitro resulted in morphological change into a non-epitheloid shape, down-regulation of E-cadherin, indicative of EMT, and in a strong induction of vascular endothelial growth factor (VEGF) expression. In contrast, in vitro exposure of MC to low-GDP solution did not lead to these phenotype changes. This could be confirmed ex vivo, as the prevalence of non-epitheloid phenotype of MC in the standard group was significantly higher with increasing PD duration and MC isolated from this group showed significantly higher levels of EMT-associated molecules including fibronectin, collagen I, VEGF, IL-8 and TGF-β levels when compared with the low-GDP group. Over time, the expression of E-cadherin also decreased in the standard but increased in the low-GDP group. In addition, the levels of EMT-associated molecules (fibronectin, VEGF and IL-8) increased in the standard but decreased in the low-GDP group. A similar trend was also observed for collagen I and for TGF-β (for the first year), but did not reach global statistical significance. Accordingly, effluent MC with non-epitheloid morphology showed significantly lower levels of E-cadherin and greater levels of fibronectin, collagen I, VEGF and IL 8 when compared with MC with epitheloid phenotype. The incidence of peritonitis did not significantly influence these results. Drop-out due to technique failure was less in the 'balance' group. The functional, renal and peritoneal evaluation of patients being treated with either standard or 'balance' fluid did not show any significant difference over time.
MC from PD effluent of patients treated with a PD fluid containing low GDP levels show fewer signs of EMT and the respective molecules than MC from patients treated with standard fluid, indicating a better preservation of the peritoneal membrane structure and a favourable outcome in patients using low-GDP fluid. It also confirms the hypothesis that the protection of EMT by GDP-reduced fluids is also present in vivo.
[show abstract][hide abstract] ABSTRACT: Phosphate control impacts dialysis outcomes. Our aim was to define peritoneal phosphate transport in peritoneal dialysis (PD) and to explore its association with hyperphosphatemia, phosphate clearance (PPhCl), and PD modality.
Two hundred sixty-four patients (61% on continuous ambulatory PD [CAPD]) were evaluated at month 12. PPhCl was calculated from 24-hour peritoneal effluent. Phosphate (Ph) and creatinine (Cr) dialysate/plasma (D/P) were calculated at a 4-hour 3.86% peritoneal equilibration test.
D/PPh correlated with D/PCr. PPhCl correlated better with D/PPh than with D/PCr. Prevalence of hyperphosphatemia (>5.5 mg/dl) was 30%. In a multiple regression analysis, only residual renal function was independently, negatively associated with hyperphosphatemia; in anuric patients, only D/PPh was an independent factor predicting hyperphosphatemia. D/PPh was 0.57 ± 0.10, and according to this, 16% of the patients were fast, 31% were fast-average, 35% were slow-average, and 17% were slow transporters. PPhCl was 37.5 ± 11.7 L/wk; it was lower in the slow transporter group (31 ± 14 L/wk). Among fast and fast-average transporters, PPhCl was comparable in both PD modalities. In comparison to automated PD, CAPD was associated with increased PPhCl among slow-average (36 ± 8 versus 32 ± 7 L/wk) and slow transporters (34 ± 15 versus 24 ± 9 L/wk).
In hyperphosphatemic, particularly anuric, patients, optimal PD modality should consider peritoneal phosphate transport characteristics. Increasing dwell times and transfer to CAPD are effective strategies to improve phosphate handling in patients with inadequate phosphate control on automated PD.
Clinical Journal of the American Society of Nephrology 11/2010; 6(3):591-7. · 5.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Bowel bacterial overgrowth syndrome (BBOS) is an important cause of gastrointestinal (GI) abnormalities. Proinflammatory cytokines (PICs) are excessively produced and accumulate because of kidney failure in dialysis patients who experience chronic infections such as BBOS. We explored the association between GL function, BBOS, and the malnutrition, inflammation, and atherosclerosis (MIA) syndrome. We studied GI malabsorption and maldigestion by analyzing fecal starch, sugar, fat, and nitrogen; intestinal protein permeability (alpha1-antitrypsin fecal clearance); and fecal chymotrypsin. We evaluated BBOS by breath hydrogen test (BHT) after a 3-day fat-and-carbohydrate-overload diet. Positive BHT was present in 10 patients, showing a high prevalence of GI macronutrient malabsorption and maldigestion, and compared with the other patients, the highest plasma levels of tumor necrosis factor alpha and interleukin 6 and lower levels of albumin and prealbumin. Those 10 patients were treated with a combination of several antibiotics, including neomycin, amoxicillin-clavulanate, and quinolones. Between 2 and 3 months later, the BHT, markers of nutrition, and PIC were re-tested. All treated patients showed an improvement in nutrition status and a lesser inflammatory pattern. The BBOS infectious process is found frequently in dialysis patients in association with GI malabsorption and maldigestion, malnutrition, and systemic inflammation. Hyperproduction of PIC because of BBOS induces MIA through a double pathway: GI disorders and deleterious systemic effects.
Advances in peritoneal dialysis. Conference on Peritoneal Dialysis 01/2010; 26:130-6.
[show abstract][hide abstract] ABSTRACT: Our aim was to evaluate the prognostic value of 2 measurements of serum adiponectin levels for all-cause mortality and cardiovascular (CV) mortality in uremic patients.
We analyzed 184 patients (19-86 years) undergoing peritoneal dialysis (n = 86) or hemodialysis (n = 98). All patients had 2 measurements of serum adiponectin levels (at baseline and after 1 year). Relationships between adiponectin and mortality were studied by means of survival analysis and Cox regression analysis.
During a median follow-up time of 31.2 months, 67 patients (36.4%) died, 26 (14.1%) as a result of CV disease. Mean survival time for CV mortality in patients with 1-year adiponectin values in the upper tertile was significantly higher than that found in patients in the middle and lower tertiles. Hazard ratios (HR) for all-cause mortality per SD change were 0.70 (95% CI, 0.50-0.98; p < 0.05) for baseline adiponectin levels and 0.68 (0.49-0.95; p < 0.05) for mean baseline and 1-year adiponectin levels. Mean adiponectin levels were also negatively related with CV mortality [HR 0.43 (0.21-0.86); p < 0.05] and CV events [HR 0.74 (0.55-0.99); p < 0.05].
In this population of dialysis patients, adiponectin seems to behave as a CV protective factor. Patients with high mean adiponectin levels had a better survival rate.
American Journal of Nephrology 05/2009; 30(3):244-52. · 2.62 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background. Endothelial dysfunction (ED) with atherosclerosis is a recognized complication of uremic patients. The importance of inflammation in ED pathophysiology has recently been proposed. The aim of this study was to analyze the role played by inflammation on ED in peritoneal dialysis (PD) patients. Methods: During 15 months, all the patients from our PD unit were followed-up. We determined nutritional, inflammatory (C-reactive protein (CRP), TNF-α and Vascular cell adhesion molecule-1 (VCAM)) and endothelial function markers at baseline and during systemic inflammation (SI). Seventeen patients were finally included due to elevation of CRP by various etiologies (4 suffered silent infection by Helicobacter pylori, 4 upper respiratory infections and 2 intestinal bacterial over-growth). They were compared with a control group (CG) with 12 PD patients who did not suffer SI. A venous occlusion test (VOT) was performed to stimulate the endothelium. Endothelial function was assessed by measuring: endothelial fibrinolytic capacity: tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI); endothelial damage markers: von Willebrand factor (vWF), thrombomodulin (TM) and nitric oxide (NO); cardiovascular (CV) risk markers: fibrinogen, lipoprotein(a) and homocysteine (Hcy); growth factors: VCAM-1, vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF). After variable of follow-up time, CRP and TNF-α plasma levels increased. Results: We found a decrease in albumin, tPA ratio (post VOT/pre-VOT) and nitrate (NO3)-ratio. PAI, TM, Lp(a) and TGF-β Increase. A positive linear correlation between Hcy and PDGF was found, suggesting a pro-atherogenic environment. The CG did not show changes in the studied parameters. Conclusions: In PD patients, systemic inflammation induces endothelial dysfunction estimated by elevation of endothelial damage markers. Pro-inflammatory cytokines are associated with elevations in procoagulable and proatherosclerotic mediators in plasma.
[show abstract][hide abstract] ABSTRACT: Ghrelin is a recently discovered protein hormone mainly synthesized in the gastric endocrine cells. This hormone not only is a potent growth hormone secretagogue but also is involved in the regulation of food ingestion and energy metabolism. Derangements in ghrelin secretion in patients with chronic renal failure (CRF) have not been fully evaluated.
Our aim has been to quantify serum concentrations of total ghrelin in a group of patients with CRF on chronic therapy with both haemodialysis (HD) and peritoneal dialysis (PD) in comparison with a group of patients on conservative management (predialysis).
We studied 68 CRF patients treated by HD (n = 30, 16 men, age 61.2 +/- 1.8 years) and PD groups (n = 38, 21 men, age 54.4 +/- 1.7 years). A group of 19 uraemic patients on conservative management served as the control. Serum concentrations of ghrelin, leptin, insulin, IGF I and GH were measured in all subjects.
Patients undergoing HD showed similar concentrations of ghrelin in comparison with the control group (9491 +/- 787 vs 9280 +/- 918 pg/ml, NS). However, PD patients exhibited baseline ghrelin concentrations significantly lower than those found in patients on conservative management (3230 +/- 216 pg/ml, P < 0.0001). Men and women showed similar serum ghrelin levels in both HD (9845.9 +/- 1071 vs 9085 +/- 1194 pg/ml) and PD patients (3214 +/- 297 vs 3250 +/- 324 pg/ml). Hypertension and diabetes mellitus did not influence ghrelin levels. Serum GH levels were positively correlated with serum ghrelin concentrations in both HD (r = 0.46, P < 0.05) and PD (r = 0.53, P < 0.001) patients; however, no relationships between ghrelin, leptin, insulin and IGF I were found.
These results suggest that PD is accompanied by a striking decrement in baseline ghrelin concentrations in comparison with values found both in HD and control patients. Further studies are necessary to determine mechanisms involved in ghrelin regulation in uraemic patients.
[show abstract][hide abstract] ABSTRACT: Studies on the evolution of peritoneal transport during the first year of peritoneal dialysis (PD) are scarce and their results are contradictory. The aim of the present study was to analyse the evolution of peritoneal transport and residual renal function during the first year on PD, and to determine the factors that may influence them.
We studied 249 patients on continuous ambulatory PD with glucose exchange solutions (117 men, 132 women, mean age 51.9+/-16 years) 59 of whom had diabetes (25 type I). At baseline and after 1 year, we determined the mass transfer coefficients of urea (U-MTAC) and creatinine (Cr-MTAC), net ultrafiltration and residual renal function.
Residual renal function decreased significantly during the first year (from 3.9+/-2.8 to 2.4+/-2.2 ml/min, P<0.001). Both U-MTAC and Cr-MTAC decreased after 1 year [U-MTAC from 22.7+/-7.8 to 20.7+/-6.6 ml/min (P<0.001), Cr-MTAC from 10.5+/-5.3 to 10.1+/-4.6 ml/min (NS)]. The ultrafiltration capacity increased significantly (from 923+/-359 to 987 U 341 ml/4 h, P<0.001). The evolution of MTAC values was independent of age, sex, diabetes and amount of hypertonic glucose used. When patients were grouped according to their initial Cr-MTAC, we observed a tendency toward normalization of the parameters of peritoneal function. Patients with peritonitis (n = 88) showed a first year increase in Cr-MTAC, which was significantly higher than in patients without peritonitis (11.1+/-5 vs 9.5+/-4.2, P<0.01). Ultrafiltration decreased in patients with more than four accumulated days of peritonitis (from 1062+/-447 to 1024+/-340 ml/4 h, NS); it increased in patients without peritonitis.
The peritoneal transport parameters tended toward normalization during the first year on PD, mainly with a decrease of small solute transport and an increase of ultrafiltration capacity. This evolution is independent of age, gender, diabetes and higher exposure to glucose in PD solutions. Peritonitis was the only independent factor that affected peritoneal function during the first year on peritoneal dialysis.
[show abstract][hide abstract] ABSTRACT: High levels of some adipocytokines have been reported in patients with chronic renal failure, but little information is available on adipocytokine concentrations in uraemic patients under different modalities of therapy. Our aims were (1) to quantify the serum concentrations of leptin, adiponectin and resistin in uraemic patients on peritoneal dialysis (PD) and haemodialysis (HD), in comparison with patients on conservative management, and (2) to study the relationships between adipocytokine levels and previous atherosclerotic vascular disease.
We studied 82 dialysis patients treated by PD (n = 44, 23 males and 21 females, mean age 54.4 +/- 1.8 years) or HD (n = 38, 22 males and 16 females, age 60.8 +/- 1.6 years). A group of 19 uraemic patients on conservative management served as the control. Serum concentrations of leptin, adiponectin and resistin were measured in all subjects. Information on vascular disease (cerebral vascular, peripheral vascular and heart disease) was obtained from a detailed medical history.
PD patients showed significantly higher serum leptin concentrations [median (interquartile range), 28.7 (13.0-71.9) microg/l] than those found in patients on HD [9.7 (4.7-31.9) microg/l, P < 0.01] or in conservative management [5.9 (4.3-38.6) microg/l, P < 0.05]. Adiponectin concentrations were similar in the three groups of patients (mean +/- SEM, 48.0 +/- 4.5 mg/l in PD, 57.7 +/- 4.4 mg/l in HD, and 44.4 +/- 7.0 mg/l in controls, NS). Patients treated by both PD and HD exhibited resistin concentrations significantly higher than those found in controls (26.3 +/- 0.99 and 27.5 +/- 1.4 microg/l, respectively, vs. 17.3 +/- 1.0 microg/l, P < 0.001). Leptin concentrations were positively correlated with body mass index (BMI) (r = 0.287, P < 0.01) and adiponectin levels were negatively related to BMI (r = -0.416, P < 0.001) and the homeostatic model assessment (HOMA-R) index (r =-0.216, P < 0.05). Leptin, adiponectin and resistin levels in patients with previous vascular events were similar to those found in patients without these complications. Logistic regression analysis did not demonstrate any relationship between serum adipocytokine concentrations and the presence of vascular disease of any type. A significant relationship between resistin and heart disease [odds ratio (OR) 1.80 (1.03-3.15), P = 0.039] was found when analysing subgroups of patients.
These data suggest that leptin levels are higher in PD patients, and resistin levels are higher in PD and HD patients in relation to patients on conservative management, whereas adiponectin concentrations are similar in the three groups. These results do not support the presence of a clinically relevant relationship between adipocytokines and previous episodes of vascular disease in the whole population or in patients classified in subgroups, with the only exception of a relationship between resistin levels and heart disease.
[show abstract][hide abstract] ABSTRACT: Anorexia is a frequent complication of uraemic syndrome, which contributes to malnutrition in dialysis patients. Uraemic anorexia has been associated with many factors. This paper reviews the current knowledge about mechanisms responsible for uraemic anorexia, the treatments and new drugs used to control the loss of appetite. Traditionally, anorexia in dialysis patients has been considered as a sign of uraemic toxicity, therefore, two hypotheses have been proposed, the ‘middle molecule’ and ‘peak-concentration’ hypotheses, both of which are still unproved. Recently, our group proposed the tryptophan-serotonin hypothesis, which is based on a disorder in the amino acid profile acquired in the uraemic status. This is characterised by low concentrations of large neutral and branched chain amino acids (LNAA/BCAA) in the cerebrospinal fluid. This situation permits a high level of tryptophan transport across the blood-brain barrier, causing an increase in the synthesis of serotonin (responsible for appetite inhibition). There are two main treatment targets for anorexia in dialysis patients. The first is to decrease the free plasma tryptophan concentration and transport across the blood brain barrier to the cerebrospinal fluid, thus decreasing the intracerebral serotonin levels. Nutritional formulae enriched with LNAA and BCAA have this effect. Secondly, plasma levels of cytokines with cachectin effect (TNF-α), should be decreased. This also induces a decrease in LNAA and BCAA levels. In this group are megestrol acetate, anti-TNF-α antibodies, thalidomide, pentoxifyilline, n-3 fatty acids and possibly nandrolone decanoate. Additionally, other targets should be explored including antagonists of cholecystokinin (a potent anorexigen retained by renal failure), analogues of neuropeptide Y (the most potent orexigen), cannabinoids, cyproheptadine, hydrazine sulfate. In conclusion, uraemic anorexia is a complex complication associated with malnutrition, high morbidity and mortality. The pharmacological treatment should address key points in the pathogenesis of uraemic anorexia, reducing intra-cerebral concentration of serotonin with LNAA/BCAA oral diet formulae and the plasma levels of pro-inflammatory molecules. Others forms of treatment should also be explored.
Expert Opinion on Pharmacotherapy 02/2005; 2(11):1825-1838. · 2.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: The GH/IGF axis is altered in chronic renal failure (CRF). CRF patients usually show normal or high serum concentrations of GH and IGF-I, whereas all IGF binding proteins (IGFBP-1 to -6), except IGFBP-5, considerably increase with declining renal function. The aims of the present study were to quantify serum concentrations of GH, IGF-I, IGFBP-1 and IGFBP-3 in a group of patients with CRF, and determine whether there were differences according to the type of dialysis, that is, peritoneal dialysis (PD) and haemodialysis (HD).
A cross-sectional study in the setting of a dialysis unit of a general hospital.
We studied 108 dialysis patients treated by PD (n = 54, 32 males and 22 females, mean age 61.0 +/- 1.4 years) or HD (n = 54, 31 males and 23 females, age 62.6 +/- 1.5 years). A group of 42 healthy subjects of similar age, sex and body mass index (BMI) served as the control group. Baseline serum concentrations of GH, insulin, IGF-I, IGFBP-1 and IGFBP-3 were measured in all patients and control subjects.
Fasting serum concentrations of IGF-I and its binding proteins (IGFBP-1 and IGFBP-3) were significantly higher in dialysis patients than in subjects with normal renal function. IGF-I (248.9 +/- 23.4 vs. 205.5 +/- 15.5 micro g/l, NS), IGFBP-3 (5.6 +/- 0.4 vs. 5.5 +/- 0.2 mg/l, NS) and IGFBP-1 (36.1 +/- 5.9 vs. 44.1 +/- 6.5 micro g/l, NS) concentrations were similar in both groups of dialysis (PD vs. HD) patients. However, GH (2.3 +/- 0.3 vs. 1.1 +/- 0.1 micro g/l, P < 0.001) and insulin (40.4 +/- 4.5 vs. 30.1 +/- 3.1 micro U/ml, P < 0.05) levels were significantly higher in the PD group than in the HD group. Both groups of dialysis patients showed significantly higher levels of insulin than healthy subjects (14.7 +/- 1.9 micro U/ml, P < 0.0001 and P < 0.01 for PD and HD, respectively). In both groups of dialysis patients, IGF-I correlated inversely with IGFBP-1 (PD group r = -0.46, P = 0.0006; HD group r = -0.57, P = 0.0001) and directly with IGFBP-3 (PD group r = 0.44, P = 0.001; HD group r = 0.73, P = 0.001). No correlation between insulin and IGFBP-1 was found in any of the groups studied.
These findings demonstrate that adult dialysis patients have elevated IGF-I, IGFBP-1 and IGFBP-3 serum concentrations compared with subjects with normal renal function. Only GH and insulin show statistically significant differences in relation to type of dialysis. Finally, the negative correlation between IGF-I and IGFBP-1 and the positive correlation between IGF-I and IGFBP-3 are maintained in both groups of adult dialysis patients.
[show abstract][hide abstract] ABSTRACT: Endothelial dysfunction with atherosclerosis is a recognized complication of uremic patients. The hypoalbuminemia of peritoneal dialysis (PD) patients can induce a hypercoagulable and atherogenic state. In this study, we investigated the role played by malnutrition-inflammation syndrome on endothelial function markers in PD patients. We measured markers of nutrition [normalized protein catabolic rate (nPCR), albumin, prealbumin, insulin-like growth factor 1 (IGF-1), transferrin, and cholesterol], markers of endothelial damage and function [tissue-type plasminogen activator (tPA), thrombomodulin (TM), von Willebrand factor (vWF), and NO3 (representing NO)], markers of a coagulable state [fibrinogen and plasminogen activator inhibitor 1 (PAI-1)], markers of inflammation [tumor necrosis factor alpha (TNF alpha) and C-reactive protein (CRP)], and other endothelial injury factors [lipoprotein(a) [Lp(a)] and homocysteine]. We also performed an endothelial stimulation test consisting of right-arm venous occlusion (VO) for 10 minutes. The patients were divided into four groups according to their clinical atherosclerotic score (CAS). We studied 45 clinically stable PD patients. At baseline, statistically significant negative linear correlations were found between albumin and age (r = -0.54, p < 0.05), albumin and vWF post-VO (r = -0.54, p < 0.05), and albumin and TM (r = -0.36, p < 0.05), which are endothelial damage markers and prothrombotic factors. A positive linear correlation was seen between albumin and NO3 post-VO (r = 0.48, p < 0.05), indicating a high vasodilatation capacity. C-Reactive protein and TNF alpha showed a positive linear correlation (r = 0.5, p < 0.01). Similarly, TNF alpha showed a positive linear correlation with cardiovascular risk markers such as fibrinogen (r = 0.79, p < 0.01), PAI-1 (r = 0.44, p < 0.05), and homocysteine (r = 0.37, p < 0.05). Creatinine clearance showed a negative linear correlation with TM (r = -0.36, p < 0.05). Patients with albumin < 4 g/dL showed a lower tPA ratio, lower NO3, and a higher CRP, TNF alpha, and Lp(a) than did patients with albumin > 4 g/dL [tPA ratio: 2.1 +/- 1.56 (n = 29) vs. 2.6 +/- 2.3 (n = 16), p < 0.05; NO3: 47 +/- 27 micrograms/mL vs. 69 +/- 33 micrograms/mL, p < 0.05; CRP: 1.8 +/- 3 mg/dL vs. 1.1 +/- 1.6 mg/dL, p < 0.05; TNF alpha: 44.4 +/- 16 pg/mL vs. 36.6 +/- 21.4 pg/mL, p < 0.05; Lp(a): 55 +/- 39 mg/dL vs. 33 +/- 21 mg/dL, p < 0.05]. Patients with a worse CAS showed higher homocysteine levels and lower albumin values. Those relationships were maintained in both periods of the study. We found no relationships between dialysis dose and endothelial function markers. In conclusion, malnutrition-inflammation syndrome may contribute to endothelial dysfunction and, consequently, to prothrombotic and proatherogenic processes in PD patients.
Advances in peritoneal dialysis. Conference on Peritoneal Dialysis 02/2003; 19:240-5.
[show abstract][hide abstract] ABSTRACT: BACKGROUND
Hypothalamic cholinergic neurotransmission plays a major role in the regulation of GH secretion. Pyridostigmine, a cholinesterase inhibitor, is able to decrease hypothalamic somatostatinergic tone and release GH in normal subjects. Blockade of muscarinic receptor with pirenzepine blunts the GH release in several clinical situations. However, little information is available on the role played by central cholinergic pathways in GH regulation in uraemic patients.OBJECTIVE
We aimed to assess GH responses to GHRH after pretreatment with pyridostigmine and pirenzepine in a group of uraemic patients undergoing peritoneal dialysis (PD). GH responses of the patients treated with recombinant human erythropeitin (rhEPO) were compared to patients without treatment.DESIGNWe studied 14 male patients on PD and nine control subjects. All subjects underwent three endocrine test in random order after an overnight fast. Each subject received GHRH (100 μg, i.v. in bolus at 0 minutes). Sixty minutes before the injection of GHRH subjects were given oral placebo, pyridostigmine (120 mg), or pirenzepine (100 mg).MEASUREMENTSBlood samples for GH were collected at −60, 0, 15, 30, 45, 60 and 90 minutes The hormonal secretory responses were studied by a time-averaged (area under the curves, AUC) and time-independent (peak values) analysis.RESULTSBaseline GH concentrations were similar in patients and controls. GH responses to placebo plus GHRH were also comparable in patients and controls (peak 26.6 ± 3.8 vs. 33.2 ± 4.4 mU/l, AUC 28.2 ± 3.4 vs. 27.8 ± 4.6 mU/h/l). Pyridostigmine administration induced a significant potentiation of GH responses to GHRH both in patients (peak 43.2 ± 5.2 mU/l, AUC 47.6 ± 6.0 mU/h/l; P < 0.01) and in control subjects (peak 79.2 ± 8.6 mU/l, AUC 78.0 ± 9.4 mU/h/l; P < 0.01). However, the increment in GH peak and AUC was significantly (P < 0.05) greater in controls in relation to values found in patients. Pirenzepine administration induced an abolishment of GH release after GHRH stimulation both in PD patients (peak 5.4 ± 2.6 mU/l, AUC 6.0 ± 2.4 mU/h/l; P < 0.01) and in healthy controls (peak 3.8 ± 0.6 mU/l, AUC 4.0 ± 0.4 mU/h/l; P < 0.05). Responses to pyridostigmine plus GHRH and pirenzepine plus GHRH were similar in patients on chronic therapy with recombinant human erythropeitin and in patients without rhEPO therapy.CONCLUSION
These results suggest that the cholinergic regulation of GH release is preserved in uraemic patients on peritoneal dialysis. The significantly lower increase in GH response to GHRH induced by pyridostigmine suggests that cholinergic stimulatory tone is attenuated in patients in relation to control subjects. Long-term therapy with rhEPO seems not to affect GH responses to cholinergic stimulation or blockade.
[show abstract][hide abstract] ABSTRACT: Abstract Sustained peritoneal inflammation, secondary to peritoneal dialysis (PD) treatment, induces a reparative process. This process is carried out by submesothelial fibroblasts and is responsible for many ofthe peritoneal structural anomalies observed during PD. Peritoneal fibrosis, mesothelial loss, vasculopathy and angiogenesis are common ,consequences of PD