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.

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.

Epidermal growth factor and transforming growth factor alpha stimulate or inhibit proliferation of a human renal adenocarcinoma cell line depending on cell status: differentiation of the two pathways by G protein involvement.

Transforming growth factor alpha production by renal tumors, acting through the epidermal growth factor receptor, has been implicated in malignant transformation by studies which compared gene expression in neoplastic and normal human tissue. We sought confirmation of this hypothesis by measuring the growth responses of a human renal tumor cell line to the addition of epidermal growth factor and transforming growth factor alpha. Surprisingly, it was found that both growth factors could induce either mitogenic or inhibitory signals depending on the growth status of the cultures. Confluent cultures were stimulated by both growth factors, and nonconfluent cultures were inhibited, as determined by thymidine incorporation, cell cycle analysis, and direct cell counting. These signals appear to use different transduction pathways, as growth factor induced inhibition was reversed by Bordetella pertussis toxin (which affects G protein signaling), whereas the stimulatory effects were not reversed. Two clones isolated from these cells responded in the same manner as the main cell isolate. These data show that the same cell may display opposite responses to equivalent concentrations of the same growth factor, depending on the transduction pathway used after triggering by receptor occupancy of either ligand (epidermal growth factor or transforming growth factor alpha).

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.

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.

Protein catabolic rate determination from a single measurement of dialyzed urea.

Protein catabolic rate (PCR, in g protein/kg/day) for anuric patients can be accurately determined without blood sampling by equating urea generation over 7 days to the urea dialyzed in the three dialyses of this period as measured by partial dialysate collection (PDC) or with a urea monitor. The feasibility of determining the week's dialyzed urea from measurement of urea dialyzed in a single session, obviating the need to monitor three consecutive dialyses, was examined in a steady-state simulation of 540 anuric patients spanning the full range of dialysis parameters. It was found that the first, midweek, and last dialyses account for nearly constant fractions (37.9, 32.1, and 30.0%, respectively) of the week's urea removal, leading to equations of the form: PCR = CU/BW + 0.17 where U is the grams of urea dialyzed in the first, midweek, or final dialysis of the week, C = 2.45, 2.89, or 3.10, respectively, and BW is the patient's dry weight in kilograms. These equations were tested on 1312 weeks of PDC data gathered in 42 dialysis patients. Using the midweek U resulted in a mean absolute error in PCR < 0.05 g/kg/day when compared to PCR determined using all three of the week's U values.

Acute polyneuropathy after malathion poisoning.

We report a patient in whom intoxication with a commercial preparation of malathion led to a severe acute cholinergic crisis, protracted cardiac arrhythmias, an acute respiratory distress syndrome, and an acute sensorimotor axonal polyneuropathy. The occurrence of the polyneuropathy was associated with a novel malathion transformation product, S-(1-ethoxycarbonyl, 2-isopropoxycarbonyl) ethyl 0,0-dimethyl phosphorodithioate (isopropylmalathion), an impurity present in the pesticide residue. The role of isopropylmalathion in the pathophysiology of the polyneuropathy remains to be determined.

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.

[Hypertension and stenosis of the graft artery: effects of conversion enzyme inhibition]. / Hypertension artérielle et sténose de l'artère du greffon: effets de l'inhibition de l'enzyme de conversion.

The use of angiotensin converting enzyme inhibitors may lead to reversible renal insufficiency in transplant patients with transplant renal artery stenosis (TRAS). We assessed acute effects of captopril (50 mg, p. os) in 7 cadaver kidney recipients (mean age: 35.6 +/- 4 yrs) with TRAS, 9 to 46 mo after transplantation. All patients were treated by prednisolone and azathioprine. After captopril administration, mean arterial pressure decreased from 127 +/- 6 to 119 +/- 7 mmHg, effective renal plasma flow from 152 +/- 19 to 118 +/- 19 ml/min/1.73 m2, glomerular filtration rate from 59 +/- 8 to 39 +/- 10 ml/min/1.73 m2 and filtration fraction from 0.39 +/- 0.02 to 0.32 +/- 0.07. Among the 7 patients, 2 developed immediate and transient anuria; 4 presented a net decrease of GFR, only one had stable GFR. This patient was chronically treated by captopril; as BP was not controlled, furosemide (40 mg p. os) was added. Serum creatinine increased from 180 to 250 mumol/l. Percutaneous angioplasty was done without decrease in BP; however, treatment by captopril and furosemide could be reinstitued without deterioration in renal function. We conclude that: acute renal failure in kidney graft recipients with TRAS is frequent, but not mandatory; sodium depletion induced by diuretics enhances the fall in GFR; acute effect of captopril must be assessed in patients with TRAS before the use of this product as long term antihypertensive treatment.

[Effect of inhibition of angiotensin converting enzyme on hypertension following kidney transplantation]. / Effets de l'inhibition de l'enzyme de conversion de l'angiotensine dans l'hypertension artérielle après transplantation rénale.

The activation of the renin angiotensin system is thought to be an important factor contributing to hypertension following kidney transplantation (TX). We studied 21 hypertensive renal transplant recipients, without evidence of acute graft rejection or transplant artery stenosis, 6 to 60 months post-TX. The acute responses of mean arterial pressure (MAP) and renal hemodynamics (ERPF: effective renal plasma flow, 131I-Hippuran clearance) and function (GFR: glomerular filtration rate, creatinine clearance; UNaV: urinary sodium excretion rate) to converting enzyme inhibition (CEI) by captopril were assessed. CEI induced a decrease in MAP (118 +/- 2 to 110 +/- 2 mmHg), renal resistance (RR: 0.27 +/- 0.02 to 0.21 +/- 0.01) and filtration fraction (FF: 0.31 +/- 0.02 to 0.23 +/- 0.01). ERPF (307 +/- 24 to 333 +/- 18 ml/min/1.73 m2) and GFR (88 +/- 5 to 78 +/- 5 ml/min/1.73 m2) were not significantly changed. UNaV increased by 53 +/- 24 mumol/min. Changes in MAP (r = -0.66), ERPF (r = 0.74) and FF (r = -0.88) were significantly correlated with the log of control plasma renin activity (PRA). In 10 patients with an increase of ERPF (range: + 30 to + 70%) and no change in GFR, the activated renin system could originate from the recipient's own kidneys. In the remaining 11 patients, CEI was associated with no increase in ERPF (change: + 2 to - 27%) and a fall in GFR, a response suggesting a possible intrarenal vascular damage. These results indicate that RAS participates in the regulation of systemic and renal vascular tone, with a possible predominant effect on efferent glomerular arteriole.

[Neurologic manifestations in Wolfram's syndrome]. / Complications neurologiques au cours du syndrome de Wolfram.

Wolfram's syndrome, also known as DIDMOAD syndrome, includes juvenile diabetes mellitus and optic atrophy variously associated with diabetes insipidus and deafness. We describe the neurological findings in 5 patients with Wolfram's syndrome. All patients had a neurological examination and were subjected electrophysiological and brain imaging including CT scan and, in one patient, MRI. There were two pairs of brothers and a sporadic case with paternal consanguinity suggesting recessive inheritance. Neurological abnormalities were found in four patients including dysarthria, seizures, anosmia, nystagmus, ataxia and changes in the electroencephalograms, electroretinograms and evoked potentials. In contrast with previous reports, four patients had abnormal brain CT scan with prominent atrophy of the brainstem. In the patient studied with NMR, severe brainstem and cerebellar atrophy was found. These neuroradiological findings are reminiscent of those described in olivopontocerebellar atrophy and are in agreement with previous pathological studies. We conclude that Wolfram's syndrome includes phenotypical manifestations of olivopontocerebellar atrophy. This reinforces the opinion that olivopontocerebellar atrophy is a nonspecific syndrome of varied causes.

[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.

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.

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.