A reliable method to assess the water permeability of a dialysis system: the global ultrafiltration coefficient.

Background: Recent randomized controlled trials suggest that sufficiently high convection post-dilutional haemodiafiltration (HC-HDF) improves survival in dialysis patients, consequently this technique is increasingly being adopted. However, when performing HC-HDF, rigorous control systems of the ultrafiltration setting are required. Assessing the global ultrafiltration coefficient of the dialysis system [GKD-UF; defined as ultrafiltration rate (QUF)/transmembrane pressure] or water permeability may be adapted to the present dialysis settings and be of value in clinics. Methods: GKD-UF was determined and its reproducibility, variability and influencing factors were specifically assessed in 15 stable patients routinely treated by high-flux haemodialysis or HC-HDF in a single unit. Results: GKD-UF invariably followed a parabolic function with increasing QUF in dialysis and both pre- and post-dilution HC-HDF (R2 constantly >0.96). The vertex of the parabola, GKD-UF-max and related QUF were very reproducible per patient (coefficient of variation 3.9 ± 0.6 and 3.3 ± 0.3%, respectively) and they greatly varied across patients (31­42 mL/h−1/mmHg and 82­100 mL/min, respectively). GKD-UF-max and its associated QUF decreased during dialysis treatment (P < 0.01). The GKD-UF-max decrease was related to weight loss (R2 = 0.66; P = 0.0015). Conclusions: GKD-UF is a reliable and accurate method to assess the water permeability of a system in vivo. It varies according to dialysis setting and patient-related factors. It is an objective parameter evaluating the forces driving convection and identifies any diversion of the system during the treatment procedure. It is applicable to low- or high-flux dialysis as well as pre- or post-dilution HDF. Thus, it may be used to describe the characteristics of a dialysis system, is suitable for clinical use and may be of help for personalized prescription.

Levels of circulating endothelial progenitor cells are related to uremic toxins and vascular injury in hemodialysis patients.

BACKGROUND: Patients suffering from chronic kidney diseases (CKD) exhibit cardiovascular diseases and profound endothelial dysfunction. CKD patients have reduced numbers of endothelial progenitor cells, but little is known about the factors influencing these numbers. OBJECTIVES: Among these factors, we hypothesized that uremic toxins and vascular injury affect endothelial progenitor cells. PATIENTS/METHODS: Thirty-eight hemodialysis patients were investigated and compared with 21 healthy controls. CD34+CD133+ immature progenitors, CD34+KDR+ endothelial progenitors cells (EPC) and myeloid EPC (mEPC) were counted in peripheral blood. Levels of uremic toxins beta(2)-microglobulin, indole-3 acetic acid, indoxylsulfate, p-cresylsulfate and homocysteine were measured. Vascular injury was assessed in hemodialysis (HD) patients by measuring aortic pulse wave velocity and plasma levels of endothelial microparticles. In vitro experiments were performed to study the effect of uremic toxins on apoptosis of progenitor cells. RESULTS AND CONCLUSIONS: CD34+CD133+ immature progenitor cell number was negatively correlated with the levels of uremic toxins beta(2)-microglobulin and indole-3 acetic acid. In vitro, indole-3 acetic acid induced apoptosis of CD133+ cells. These data indicate uremic toxins have a deleterious role on progenitor cells, early in the differentiation process. Moreover, mEPC number was positively correlated with markers of vascular injury-pulse wave velocity and endothelial microparticle levels. This suggests that vascular lesions could stimulate progenitor cell mobilization, even in a context of reduced EPC induced by CKD. In conclusion, uremic toxins and vascular injury appear to affect endothelial progenitor cell biology in CKD.

Ischemic postconditioning prevents ischemic acute renal failure.

INTRODUCTION: Delayed graft function (DGF), a frequent complication after kidney transplantation, decreases graft survival. Ischemia/reperfusion (I/R) injuries play a major role in DGF pathophysiology. Because ischemic postconditioning (IP) is efficient to prevent myocardial I/R injuries and reduce infarct size, we sought to describe renal effects of IP. MATERIALS AND METHODS: Swiss mice were divided into three groups after left nephrectomy. Thirty minutes of right kidney ischemia followed by three cycles of 30 seconds of ischemia and reperfusion (IP group: n = 12) versus immediate reperfusion (n = 7). Left nephrectomized and right kidney sham operated mice were used as control groups (n = 6). Mice were followed for an 8-day survival analysis. Serum levels of creatinine and protein as well as weights were determined 2 days before and at days 2 and 8 after surgery. RESULTS: IP improved kidney function on day 2; the mean serum creatinine level was 1.25 +/- 0.71 versus 2.9 +/- 1.3 mg/dL in the immediate reperfusion group (P < .02). We also observed a trend toward increased animal survival (25% vs. 0% in the immediate reperfusion group; P = .10). Despite a significant increase in proteinuria among all groups, there was no significant difference. CONCLUSION: In a mouse model, IP seems to prevent postischemic acute renal failure after 30 minutes of kidney ischemia.

Chronic kidney disease as cause of cardiovascular morbidity and mortality.

To make an evidence-based evaluation of the relationship between kidney failure and cardiovascular risk, we reviewed the literature obtained from a PubMed search using pre-defined keywords related to both conditions and covering 18 years (1986 until end 2003). Eighty-five publications, covering 552 258 subjects, are summarized. All but three studies support a link between kidney dysfunction and cardiovascular risk. More importantly, the association is observed very early during the evolution of renal failure: an accelerated cardiovascular risk appears at varying glomerular filtration rate (GFR) cut-off values, which were >/=60 ml/min in at least 20 studies. Many studies lacked a clear definition of cardiovascular disease and/or used a single determination of serum creatinine or GFR as an index of kidney function, which is not necessarily corresponding to well-defined chronic kidney disease. In six studies, however, chronic kidney dysfunction and cardiovascular disease were well defined and the results of these confirm the impact of kidney dysfunction. It is concluded that there is an undeniable link between kidney dysfunction and cardiovascular risk and that the presence of even subtle kidney dysfunction should be considered as one of the conditions necessitating intensive prevention of this cardiovascular risk.

[Sequential protocols with thymoglobuline and delayed introduction of calcineurin: effects on renal function in renal transplant recipients with non immunological risk and low risk of delayed graft function]. / Protocoles séquentiels avec induction par thymoglobulines et introduction retardée des inhibiteurs de la calcineurine: effets sur la fonction du greffon chez le transplanté rénal sans facteur de risque.

Induction therapy with thymoglobuline significantly decreases the risk of acute rejection, particularly in high immunological risk patients, in combined transplantations and in pediatric renal transplantation. After the introduction of cyclosporin in the 1980's and the recognition of its potential nephrotoxicity, induction therapy with delayed introduction of cyclosporin (sequential protocols) have became very popular in many transplant centers and are now used even in low-immunological risk patients. The aim of the present study was to assess the recovery of renal function in low-immunological risk patients receiving a sequential protocol versus those receiving a calcineurin inhibitor at day 1. Among patients receiving their first transplant in our center between January 1999 and June 2000, we selected 72 recipients with no immunological risk and no risk of delayed graft function (DGF). 35 patients (group I) have received a sequential protocol whereas 37 patients (group II) have received a calcineurin inhibitor (Neoral or prograf) at day 1. We analysed creatinine reduction ratio, 24-hour creatinine excretion on post-transplant day 2, and serum creatinine and creatinine clearance at day 15, 30, 45, 60 and 90 post-transplant. There was no difference between groups concerning demographic, immunological or surgical parameters. The percentage of patients with immediate graft function was similar between the two groups (10 versus 9). The number of patients requiring dialysis in the first post-transplant week was also similar (8/35 versus 6/37). The day serum creatinine reached 200 micromol/l was 15 +/- 11 versus 14 +/- 12 in groups I and II respectively. Serum creatinine and creatinine clearance were similar at all time intervals. CMV disease was significantly higher in the group 1 (42% versus 18.5%; p < 0.005). Our data suggest that in patients with low immunological risk and low-risk of DGF, introduction of calcineurin inhibitors as early as the post-transplant day 1 is not deleterious for renal function recovery. These data should be confirmed by a prospective randomised trial.

[BIG-H3 protein: mutation of codon 124 and corneal amyloidosis]. / Protéine BIGH3: mutation du codon 124 et amylose cornéenne.

In 1997, a group of hereditary corneal dystrophies was related to mutations in the TGFBI (BIGH3) gene. Within this group, some corneal dystrophies present particular biochemical features in that they are characterized by corneal amyloid deposition. Contrary to clinical and genetic knowledge, the biochemical characteristics of the encoded protein (Big-h3) and the mechanisms of its amyloid conversion remain unclear. We review the current knowledge on the Big-h3 protein and focus on the behavior of the codon 124 region. We discuss this protein's mechanisms of amyloid conversion from our results and previous reports as well as from other types of amyloidosis. These data provide a better understanding of the putative processes leading to the phenotypic variations linked with their respective codon 124 mutation.

Diagnóstico etiológico del infarto cerebral en el hospital comarcal / Aetiological diagnosis of cerebral infarction in a county hospital

Introducción. Existen diversas clasificaciones etiológicas del infarto cerebral (IC) con criterios diagnósticos explícitos, pero se desconoce el grado de implantación de estos criterios diagnósticos en la práctica clínica. Objetivos. Analizar el manejo y uso de las pruebas diagnósticas en el diagnóstico etiológico del IC en dos hospitales comarcales y compararlo con las recomendaciones más utilizadas. Analizar las variables clínicas y demográficas que influyen en la no adhesión a estas recomendaciones. Pacientes y métodos. Revisamos los informes de alta de 307 casos de IC atendidos en dos hospitales comarcales entre los años 1999 y 2000 y analizamos los datos clínicos, pruebas diagnósticas y el diagnóstico emitido. Reorganizamos los diagnósticos con la utilización de las clasificaciones TOAST, Laussane, NINDS y SEN-98. Analizamos la frecuencia de utilización de las pruebas diagnósticas en cada subtipo etiológico. Resultados. Edad media: 71,3 años; 59,3 por ciento fueron varones. Se realizó TAC en el 97,1 por ciento de casos, neurosonología en 40,1 por ciento y ecocardiografía en 8,5 por ciento. El diagnóstico etiológico fue: aterotrombótico, 22,4 por ciento; cardioembólico, 10,7 por ciento; lacunar, 26 por ciento; causa inusual, 0,3 por ciento; y causa desconocida, 1,6 por ciento. En el 37,4 por ciento de casos el diagnóstico fue IC no especificado. Al reclasificar los diagnósticos según los criterios SEN-98 obtuvimos: aterotrombótico; 19,5 por ciento; cardioembólico, 2,8 por ciento; lacunar, 13,7 por ciento; y causa desconocida, 63,5 por ciento. El 0,6 por ciento fueron inclasificables. La edad, nivel de conciencia y mortalidad influyeron en la menor realización de pruebas diagnósticas. La causa más frecuente de `estudios incompletos' fue la ausencia de doppler carotídeo. Conclusiones. La adhesión a las recomendaciones para el diagnóstico etiológico del IC es baja. La realización sistemática de estudio neurosonológico mejoraría el diagnóstico etiológico del IC (AU)

Introduction. Cerebral infarction (CI) can be classified aetiologically in several different ways using explicit diagnostic criteria. However, the extent to which these diagnostic criteria are actually implemented in clinical practice is unknown. Aims. The aim of this study was to analyse the management and use of diagnostic tests in the aetiological diagnosis of CI in two county hospitals and to compare this with the most common recommendations. We also sought to analyse the clinical and demographic variables that may help to explain why these guidelines are not followed. Patients and methods. We reviewed the discharge abstracts of 307 cases of CI attended in two county hospitals between 1999 and 2000 and we analysed the clinical data, diagnostic tests and the final diagnosis. The diagnoses were reorganised using the TOAST, Laussane, NINDS and SEN-98 classifications and we analysed the frequency with which the diagnostic tests were employed in each aetiological subtype. Results. Average age: 71.3 years; 59.3% were males. CAT scans were performed in 97.1% of cases, neurosonology was used in 40.1% and echocardiography was performed in 8.5%. The aetiological diagnosis was: atherothrombotic 22.4%, cardioembolic 10.7%, lacunar 26%, unusual causes 0.3% and unknown causes 1.6%. In 37.4% of cases the diagnosis was given as unspecified CI. On reclassifying the diagnoses according to SEN-98 criteria, we obtained the following: atherothrombotic 19.5%, cardioembolic 2.8%, lacunar 13.7% and of unknown origin 63.5%. 0.6% of the cases were unclassifiable. Factors that exerted an influence on the fact that diagnostic tests were less frequently carried out included age, level of awareness and mortality. The most frequent cause of ‘incomplete studies’ was the absence of carotid Doppler. Conclusions. The guidelines for aetiological diagnosis of CI are not often followed. Systematic performance of a neurosonological study would improve aetiological diagnosis of CI (AU)

Necrotic skin lesions in a dialysis patient: a multifactorial entity.

A female dialysis patient with a consistently high serum calcium phosphate product presented with large necrotic skin lesions with ulcers. The clinical course was highly suggestive of calciphylaxis. Parathyroidectomy was followed by the healing of the lesions. New skin lesions appeared following relapse of hyperparathyroidism. Her clinical records included a long past of hypertension, which was the cause of her renal failure. She had a limited walking range and previously had presented bilateral ulcers of vascular origin. This case presents a type of lesion which bears a serious prognosis in dialysis patients. The clinical context and the presentation of the lesions are compatible with multiple etiology: vascular lesions and calciphylaxis. The documented longitudinal follow-up illustrates the importance of treating the different factors known to participate in the appearance of skin lesions in dialysis patients. Particularly, it stresses the benefit of performing parathyroidectomy, even if the parathyroid hormone level is not in the range normally accepted as requiring surgical removal of parathyroid glands.

Fiebre de origen central en el ictus / Presence of central fever during stroke

Introducción. La fiebre aparece aproximadamente en la cuarta parte de los enfermos con ictus. Aunque en la mayoría de los enfermos es infeccioso, su origen resulta difícil de demostrar en una minoría de casos. El mecanismo de la fiebre en el ictus no está aclarado, y se ha sugerido que tanto la propia lesión isquémica, bien por lesión hipotalámica o por segregación de pirógenos endógenos, sea la responsable de la hipertermia. Objetivos. Valorar la frecuencia de fiebre de origen no infeccioso durante un ictus y analizar si esta fiebre posee un patrón o características especiales que la diferenciarían de la fiebre infecciosa. Pacientes y métodos. Se evaluaron prospectivamente 103 pacientes con ictus; si presentaban fiebre, se realizaba un protocolo buscando una causa infecciosa. Se dividieron los casos en `fiebre de origen infeccioso' y `fiebre sin infección documentada' y se analizaron las características de los ictus en cada grupo y el comportamiento de la fiebre. Resultados. El 23 por ciento de los pacientes presentaron fiebre, el 33 por ciento fueron sin infección documentada. Este último grupo presentó mayor precocidad de la fiebre, mayor afectación clínica inicial, mayor mortalidad precoz, mayores temperaturas máximas y falta de respuesta al tratamiento antitérmico al compararlo con el grupo infeccioso. El resto de los parámetros estudiados no mostraron diferencias estadísticamente significativas entre ambos grupos. Conclusiones. Los pacientes con fiebre de origen no infeccioso tienen un patrón claro y definido, diferente a la fiebre de origen infeccioso. Proponemos un mecanismo central de la fiebre en dichos casos (AU)

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.

In vitro creation of amyloid fibrils from native and Arg124Cys mutated betaIGH3((110-131)) peptides, and its relevance for lattice corneal amyloid dystrophy type I.

BetaIGH3 protein has been recently involved in the pathogenesis of blinding corneal diseases, some of which have characteristic amyloid corneal deposits. The 124 codon of the betaig-h3 gene seems to be crucial for the amyloidogenicity of the protein product. We presently report an in vitro system that reproducibly forms amyloid fibrils from betaIGH3((110-131)) derived peptides. We also assessed the differences in fibril formation of two 22-amino acid peptides centered on the 124 residue: the native form and the Arg124Cys peptide (mutation linked to lattice corneal amyloid dystrophy type 1). After dialysis of Arg124Cys peptide against PBS 1/15 M pH 7.4 for 72 hours, Congo red staining and electron microscopy demonstrated the presence of abundant material fulfilling the criteria of amyloid. Quantitative analysis with thioflavine T fluorescence studies confirmed the high capacity of Arg124Cys peptide to form amyloid fibrils when compared to the native form.

BIGH3 exon 14 mutations lead to intermediate type I/IIIA of lattice corneal dystrophies.

PURPOSE: To screen the BIGH3 gene in three unrelated families with lattice corneal dystrophy (LCD), two of which disclosed a particular phenotype. METHODS: Genomic DNA was extracted from peripheral leukocytes of the affected patients and their family members. The entire coding sequence of the BIGH3 gene was screened for mutations by means of transcript analysis on total RNA isolated from peripheral leukocytes by reverse transcription-polymerase chain reaction performed with primers designed for this study. Each mutation was confirmed at the genomic level, by using published primers. RESULTS: One family that had a typical form of LCD, had the described R124C mutation in the BIGH3 gene. Two families with atypical forms of LCD were negative for the previously known mutations of the gene. Direct sequencing of the BIGH3 mRNA in the latter two families allowed us to identify two mutations located in exon 14. They consist of a 9-bp insertion at position 18851886 and one missense mutation at position 1877 of the BIGH3 gene. Three new polymorphisms were also observed. CONCLUSIONS: Two mutations different from those linked to LCD have been found in clinically distinguishable forms of this disease, intermediate between LCDs types I and IIIA. The DNA segment comprising both alterations normally encodes for a highly conserved region of the fourth internal domain of the Betaig-h3 protein, suggesting that this region may be of functional and/or structural importance. The identification of new mutations by screening of the complete BIGH3 gene and the comparative analysis of the induced modifications in betaig-h3 protein should shed light in the understanding of the molecular mechanisms underlying LCDs resulting from mutations in the BIGH3 gene, and may help to explain their phenotypic heterogeneity.

Influence of convection on small molecule clearances in online hemodiafiltration.

BACKGROUND: Dialysis efficacy is mostly influenced by dialyzer clearance. Urea clearance may be estimated in vitro by total ion clearance, which can be obtained by conductivity measurements. We have previously used this approach to assess in vitro clearances in a system mimicking predilutional and postdilutional online hemodiafiltration with a wide range of QD, QB, and ultrafiltration rates. Our current study elaborates on a formula that allows the prediction of the influence of ultrafiltration on small molecule clearances, and validates the mathematical approach both experimentally in vitro and clinically in vivo data. METHODS: Two conductivimeters in the dialysate side of an E-2008 Fresenius machine were used. HF80 and HF40 polysulfone dialyzers were used; reverse osmosis water and dialysate were used for blood and dialysate compartments, respectively. Study conditions included QB of 300 and 400 mL/min and QD of 500 and 590 mL/min, with a range of ultrafiltration rate from 0 to 400 mL/min in postdilutional hemodiafiltration and to 590 mL/min in predilutional hemodiafiltration. Urea clearances were determined in the in vivo studies, which included 0, 50, 100, and 150 mL/min ultrafiltration rates. RESULTS: The ultrafiltration rate and clearance were significantly correlated (R > 0.9, P < 0.001) and fitted a linear model (P < 0.001) in all of the experimental conditions. The following formula fitted the experimental points with an error <2% for both postdilutional and predilutional online diafiltration in vitro, respectively. K = K0 + [(QB - K0)/(QB)] x ultrafiltration rateK = K0 + [((QD x QB)/(QB + QD) - K0)/QD] x ultrafiltration rate where K is the clearance; K0 is the clearance with nil ultrafiltration rate; QD is the total dialysate produced (in commercial HDF, QD = QDi + Qinf). Since weight loss was maintained at 0, ultrafiltration rate = infusion flow. QB is the "blood" line flow. The formula was also verified in vivo in clinical postdilutional hemodiafiltration with a QB taking into account the cellular and water compartments. DISCUSSION: In vitro, by simply determining the clearance in conventional dialysis, the total clearance for any ultrafiltration rate may be estimated in both predilutional and postdilutional online diafiltration with an error of less than 2%. The same applies to in vivo postdilutional hemodiafiltration when the formula takes into account the cellular and water composition of blood.

alpha2-Macroglobulin, the main serum antiprotease, binds beta2-microglobulin, the light chain of the class I major histocompatibility complex, which is involved in human disease.

beta(2)-Microglobulin, a 12 kDa protein forming part of the class I HLA (histocompatibility locus antigen) major histocompatibility complex, has been used as a prognosis factor for multiple myeloma and as a marker of renal function, and has been shown to be involved in the pathogenesis of dialysis-related amyloidosis. alpha(2)-Macroglobulin has the ability to bind a wide range of physiologically important molecules, thereby influencing their metabolic impact. In this study we show by Western blotting analysis that beta(2)-microglobulin binds to alpha(2)-macroglobulin in vitro. This binding was confirmed by BIAcore analysis, and was shown by ELISA to be concentration-dependent. The sequences of the binding peptides in the mature beta(2)-microglobulin molecule were identified by Spot multiple peptide synthesis and alpha(2)-macroglobulin binding studies. In conclusion, beta(2)-microglobulin interacts specifically with the universal antiprotease a(2)-macroglobulin. The identification of this interaction brings into question some of the axioms on the metabolism of beta(2)-microglobulin, and may help to explain the clinical findings observed in b(2)-microglobulin-related diseases.

Analysis of the influence of the infusion site on dialyser clearances measured in an in vitro system mimicking haemodialysis and haemodiafiltration.

BACKGROUND: Blood flow (QB), dialysate flow (QD), and dialyser characteristics are the three major factors driving dialysis efficacy. Haemodiafiltration has added an increased convective volume to increase efficacy. We aimed to assess the influence of the infusion site of the replacement fluid in an in vitro system emulating haemodiafiltration. METHODS: An in vitro system allowing us to control the dialysate temperature, concentration gradient, the flow of both dialyser sides over a range wider than that compatible with clinic, was set to evaluate the influence of the different parameters on dialysis efficacy. The total ion clearance was used as an accepted method for small molecule clearance assessment. Cellulose triacetate (CT190C, Baxter; FB170U, Nipro) and polysulfone (HF80, Fresenius) dialysers were included in the study. Dialysis as well as on-line diafiltration both with pre- and postdilutional infusion were assessed. The experimental conditions presented in this study included QD 620 and 970 ml/min. The convective flows ranged from 50 to 200 ml/min. RESULTS: For a QD = 620 ml/min and a QB = 350 ml/min the total ion clearance ranged from 269 to 274 for HF80, from 291 to 294 for FB170 and from 294 to 302 for CT190. The variability of the measurements was very low (SD < 1%). Total ion clearance increased by 17-21% when QB was raised from 300 to 400 ml/min. Increasing QD from 420 to 970 ml/min (for QB = 350 ml/min), resulted in an increase in total ion clearance which was more marked at lower QD (from 420 to 620 ml/min) and plateaued thereafter (from 620 to 970 ml/min). Postdilutional on-line diafiltration with 100 ml/min of infusate resulted in an additional increase in total ion clearance of 5.4-8.6%. This increase was proportional to the infused volume. On the contrary, predilutional on-line diafiltration resulted in a decrease in total ion clearance which was also proportional to the infused volume (between -5.1 and -6.9% at 100 ml/min infusion volume and -9.7 to -12.9% at 200 ml/min). CONCLUSIONS: The present in vitro system provided accurate and reproducible results on dialyser clearances. Our experiments confirmed previous studies on the influence of QB and QD on dialyser efficacy. Further, they show that the proportional increase in postdilutional on-line diafiltration is lesser than that previously reported. More importantly, they also show that pre-dilution infusion in high efficiency systems results in a drop in dialyser clearance compared to dialysis alone, again proportional to the infusion rate. Thus, increasing the convective flow may increase dialysis efficacy even more than increasing QD alone. However, the choice of infusion site is crucial to obtaining this benefit in small molecule clearances.