Uremic State Research Articles

Nepsilon-(carboxymethyl)lysine, Nepsilon-(carboxyethyl)lysine and vascular cell adhesion molecule-1 (VCAM-1) in relation to peritoneal glucose prescription and residual renal function; a study in peritoneal dialysis patients.

Advanced glycation end products (AGEs) may contribute to peritoneal and cardiovascular damage in peritoneal dialysis (PD) patients, possibly in part by over-expression of vascular cell adhesion molecule-1 (VCAM-1). It has been suggested that peritoneal glucose load, oxidative stress, as well as the uraemic state itself may lead to an increased formation of AGEs. Aims of the present study were first to investigate the relation between residual glomerular filtration rate (rGFR), malondialdehyde (MDA) as a marker of lipid peroxidation, and peritoneal glucose prescription and absorption with serum levels of VCAM-1 and with the well characterized AGEs N(epsilon)-(carboxymethyl)lysine (CML) and N(epsilon)-(carboxyethyl)lysine (CEL), as well as with CML and CEL in peritoneal effluent. CML and CEL were measured by tandem mass spectroscopy, MDA by HPLC, and VCAM-1 by ELISA in 37 stable PD patients (age 54 +/- 12 years; time on PD 25 +/- 18 months). CML and CEL were also measured after a 4-month interval. rGFR was independently related to CML both in serum (r = -0.66; P<0.001) and effluent (r = -0.62; P<0.001), whereas peritoneal glucose prescription and absorption were, respectively, related to CML in serum and effluent (r = 0.49; P<0.001 and r = 0.44; P<0.01). Relationships were comparable when assessed after the follow-up period. Peritoneal glucose absorption (r = 0.37; P<0.05), but not rGFR, was related to CEL in serum. The relation between peritoneal glucose prescription and CML in effluent lost significance when rGFR was added to the multi-regression model. Both rGFR (r = -0.40; P<0.05) and peritoneal glucose absorption (r = 0.37; P<0.05) were associated with VCAM-1 expression, which was itself weakly related only to CML in effluent (r = 0.38; P<0.05). MDA was not related to any parameter. Peritoneal glucose prescription and absorption, as well as rGFR are related to serum and effluent levels of CML and to VCAM-1 expression in serum, whereas peritoneal glucose absorption was related to serum levels of CEL. Still, the effect of rGFR, which does not appear to be mediated through lipid peroxidation pathways, on effluent levels of CML appears to outweigh the effect of the PD treatment. Even small differences in residual renal function in patients already on dialysis therapy are related to large variations of CML in serum and the peritoneal cavity.

Supplemented very low protein diet ameliorates responsiveness to erythropoietin in chronic renal failure

The aim of this study was to evaluate the relationship between uremic state and erythropoiesis in patients with predialytic chronic renal failure (CRF). We monitored for 2 years the erythropoietin (EPO) requirement in patients with advanced CRF (creatinine clearance < or =25 mL/min), randomized to either low protein diet (LPD) group (0.6 g/kg body weight/day, N = 10) or very low protein diet (VLPD) group (0.3 g/kg body weight/day, N = 10) supplemented with a mixture of ketoanalogs and essential amino acids, both kept at target hemoglobin levels. The achieved protein intake after 6 months was 0.79 +/- 0.02 g/kg body weight/day and 0.50 +/- 0.02 g/kg body weight/day in LPD and VLPD, respectively; such a difference was maintained up to the end of follow up. The final hemoglobin values did not differ from the basal values in either group (11.5 +/- 0.2 g/dL and 11.5 +/- 0.3 g/dL). EPO dose, that was similar at baseline (62.4 +/- 9.6 UI/kg body weight/week and 61.8 +/- 8.8 UI/kg body weight/week subcutaneously), remained unchanged in LPD but progressively decreased in VLPD down to the final value of 41.2 +/- 7.0 UI/kg body weight/week (P < 0.0001 vs. basal and LPD). VLPD was associated with a decrease of urinary excretion and serum levels of urea nitrogen and phosphate; however, EPO requirement was not correlated with the changes of these parameters. On the contrary, the variation of EPO dose directly correlated with the modification of parathyroid hormone (PTH) levels, that diminished from 229 +/- 55 pg/mL to 118 +/- 16 pg/mL (P < 0.0001) in VLPD and did not change in LPD. In patients with advanced CRF, an effective decrease of protein intake of 0.3 g/kg body weight/day induces a reduction of about 35% of the EPO dose required to maintain the target hemoglobin levels. This effect appears dependent on the correction of a moderate secondary hyperparathyroidism.

Clinical presentation and outcome of severe acute respiratory syndrome in dialysis patients

There was a major outbreak of severe acute respiratory syndrome (SARS) affecting more than 300 patients occurring in a private housing estate in Hong Kong, in which an infected renal patient was suspected to be the primary source. It is unknown whether renal patients would represent a distinct group of patients who share some characteristics that could predispose them to have higher infectivity. In this context, we have encountered 4 dialysis patients contracting SARS in a minor outbreak, which involved 11 patients and 4 health care workers, in a medical ward of a regional hospital. Of these 4 dialysis patients, 1 patient was receiving hemodialysis while the other 3 patients were on continuous ambulatory peritoneal dialysis. Fever and radiological changes were their dominant presenting features. All were having positive results for SARS-associated coronavirus ribonucleic acid by reverse transcriptase-polymerase chain reaction performed on their nasopharyngeal aspirates or stool samples. It appeared that treatment with high-dose intravenous ribavirin and corticosteroids could only resolve the fever, but it could not stop the disease progression. All 4 patients developed respiratory failure requiring mechanical ventilation on days 9 through 12. At the end, all of the patients died from sudden cardiac arrest, which was associated with acute myocardial infarction in 2 cases. From this small case series, it appeared that dialysis patients might have an aggressive clinical course and poor outcome after contracting SARS. However, a large-scale study is required to further examine this issue, and further investigation into the immunologic abnormalities associated with the uremic state in this group of patients is also warranted.

Atrophy of non-locomotor muscle in patients with end-stage renal failure.

All previous histological studies of skeletal muscles of patients with renal failure have used locomotor muscle biopsies. It is thus unclear to what degree the observed abnormalities are due to the uraemic state and how much is due to disuse. The present study was undertaken to attempt to investigate this question by examining a non-locomotor muscle (rectus abdominis) in patients with end-stage renal failure. Biopsies from rectus abdominis were obtained from 22 renal failure patients (RFPs) undergoing surgical Tenchkoff catheter implantation for peritoneal dialysis and 20 control subjects undergoing elective abdominal surgery. Histochemical staining of frozen sections and morphometric analysis was used to estimate the proportion of each fibre type, muscle fibre area and capillary density. Myosin heavy chain composition was examined by SDS-PAGE. There were no differences in fibre type distribution between RFPs and controls. All RFPs showed fibre atrophy [mean cross-sectional area (CSA) 3300 +/- 1100 microm2, compared to 4100 +/- 1100 microm2 in controls (P < 0.05)]. All fibre types were smaller in mean CSA in RFPs than in controls (15, 26 and 28% for types I, IIa and IIx, respectively). These differences could not be accounted for by differences in age, gender or cardiovascular or diabetic comorbidity. Muscle fibre capillarization, expressed as capillaries per fibre or capillary contacts per fibre, was significantly less in RFPs. Since a non-locomotor muscle was examined, the effects of disuse as a cause of atrophy have been minimized. It is likely, therefore, that the decreased muscle fibre CSA and capillary density of RFPs compared to controls were due predominantly to uraemia itself.

Reduced P‐selectin expression on circulating platelets after prolonged cold preservation in renal transplantation

The uremic state in patients with terminal renal insufficiency is accompanied by a bleeding tendency connected with platelet dysfunction. Prolonged cold ischemia and inflammatory interactions between leukocytes, platelets and endothelial cells contribute to ischemia-/reperfusion (I/R) injury and may impair long-term graft survival. We evaluated the influence of the duration of cold preservation time on the expression of platelet GPIIb/IIIa and P-selectin and on the formation of leukocyte-platelet complexes after kidney transplantation. Fourteen patients undergoing kidney transplantation were divided into group I with long preservation time (26.6 +/- 1.9 h) and group II with short preservation time (8 +/- 6.1 h). Five venous blood samples (3 ml) were taken before induction of anesthesia, 12 h, 2, 7 and 14 d after transplantation. Surface expression of the GPIIb/IIIa, P-selectin and the percentage of platelet-granulocyte complexes were quantified by flow cytometry. Additionally blood from seven healthy volunteers was analyzed. GPIIb/IIIa and P-selectin expression on circulating platelets were significantly decreased in the long and the short-term graft preservation group compared with healthy volunteers. A significantly reduced P-selectin expression was found in the long-term preservation group compared with the short-term group. The percentage of platelet-granulocyte complexes also decreased in both preservation groups in the first 2 d after reperfusion and remained in this state in the long-term preservation group. Reduced expression of P-selectin on circulating platelets may be an indicator of I/R injury after prolonged kidney graft preservation.

Traditional and emerging cardiovascular risk factors in end-stage renal disease

Patients with end-stage renal disease face a particularly high risk of cardiovascular disease and total mortality. Part of their increased risk is due to a higher prevalence of established risk factors, such as arterial hypertension, diabetes, smoking, and anemia. Hypertension and diabetes have a very high prevalence in dialysis patients and play a major role in their high mortality and morbidity. Hyperparathyroidism, hyperhomocysteinemia and disordered lipid metabolism represent factors that are peculiarly altered by the uremic state. Inflammatory processes, high sympathetic activity, and the accumulation of an endogenous inhibitor of NO synthase (ADMA), have recently emerged as cardiovascular risk factors of paramount importance. Sleep apnea has been linked with nocturnal hypertension and could be implicated in the high prevalence of concentric hypertrophy of the left ventricle in these patients. Hypertension control, as well as appropriate treatment of anemia and cessation of smoking, constitutes a fundamental area of intervention in dialysis patients. It appears possible that, in the near future, control of chronic inflammatory processes of high sympathetic activity and endothelial dysfunction will further help to curb the exceedingly high cardiovascular mortality of patients on chronic dialysis treatment.

Physiologic Inhibitors of Coagulation in Patients on Chronic Hemodialysis

Patients on hemodialysis are at increased risk for bleeding and thromboses. The intriguing balance between these risks is more complex than once thought, as endogenous clotting factors and their regulators come into contact with bioincompatible dialyzer membranes, in the setting of an extracorporeal circuit of blood flow, in the face of the uremic state. In this review, we summarize the current data on the interaction between the physiologic inhibitors of coagulation and hemodialysis. Data sources and study selection were obtained from research and review articles related to the endogenous anticoagulation pathway published in English on MEDLINE from 1972 to 2002. While protein C activity and protein S antigen concentrations are increased, there is no change in antithrombin III levels during hemodialysis in relation to predialysis levels. Plasma protein Z, which has only recently been studied in uremic subjects, is increased as well. In addition, hemodialysis leads to elevated tissue factor plasminogen inhibitor, thrombomodulin, tissue plasminogen activator, and plasminogen activator inhibitor-1 activities. The potential functional significance of these observations is discussed. Finally, as erythropoietin is commonly prescribed to uremic patients and is recognized to be prothrombotic, an appraisal of its interaction with the naturally occurring anticoagulants is presented. It is apparent that we are only beginning to realize the complexity of the interplay between this myriad of serum factors and hemodialysis. Further research is needed to shed light on this underexplored area of hemodialysis.

Neuroendocrine adaptations in renal disease.

Chronic renal failure (CRF) disrupts the time-dependent secretion of multiple hormones. The present review focuses on altered pulsatile release of peptide hormones. CRF is marked by impaired tissue actions, disorderly release patterns, and relative [growth hormone (GH)] or absolute [luteinizing hormone (LH)] deficiency of secretion. At the hypothalamo-pituitary level, experimental evidence suggests that CRF reduces the synthesis and/or release of the cognate hypothalamic releasing factors, GHRH and LHRH, and enforces excessive inhibition by somatostatin. Parathyroid hormone (PTH) and insulin are secreted in both basal and pulsatile modes, wherein the latter is putatively coordinated by autonomic innervation. Amplitude and frequency-dependent adaptations of PTH and insulin outflow fail in CRF, as assessed under steady-state conditions and during metabolic drive (i.e., calcium for PTH and glucose for insulin). A common feature in CRF is a diminished mass of hormone released per burst, due in principle to attenuation of feedforward signals and/or accentuation of (unknown) feedback signals. Damping of neuronal control and/or prolonged network response times may contribute to aberrant pulse frequency, disproportionate basal (nonpulsatile) hormone release, and consistent erosion of secretory process regularity in the uremic state. The homeostatic consequences of distorted secretory dynamics, tissue resistance, impaired hormone clearance, and altered mean agonist concentrations are evident in certain therapeutic interventions, such as GH supplementation in CRF.

Asymptomatic occlusive lesions of cerebral arteries in Japanese hemodialysis patients.

While cerebrovascular diseases (CVD) are very common in hemodialysis (HD) patients, the prevalence and risk factors of asymptomatic occlusive lesions (AOL) of cerebral arteries in HD patients have not yet been elucidated. We performed cerebral magnetic resonance angiography (MRA) on 123 HD patients without symptomatic cerebrovascular disease and on 52 control subjects. On the basis of these images, we investigated the prevalence and risk factors of AOL. Stenosis greater than 25% narrowing of the cerebral arteries was found in 27 HD patients. The prevalence of AOL of cerebral arteries in HD patients was significantly higher than in the control group [27 (22.0%) versus 4 patients (7.7%), chi.2=4.2, p=0.0411]. Multiple logistic regression analysis showed that independent risk factors of AOL of cerebral arteries were uremic state, dyslipidemia, and age in all subjects and dyslipidemia and age in HD patients (R.2=0.162, p=0.0004; R.2 =0.138, p=0.0145, respectively). Our findings suggest that chronic renal failure maintained by hemodialysis increases the prevalence of AOL, and that age and dyslipidemia are also significantly associated with AOL in HD patients.

Oxidant stress in hemodialysis patients: what are the determining factors?

Oxidant stress contributes to morbidity in hemodialysis patients. Three possible causes of oxidant stress have been suggested: the uremic state, the dialyzer membrane, and bacterial contaminants from the dialysate. Oxidant stress occurs in uremia before dialysis therapy is initiated, as evidenced by increased production of reactive oxygen species, increased levels of oxidized plasma proteins and lipids, and decreased antioxidant defenses. It has been proposed that increased production of reactive oxygen species during hemodialysis is also an important contributor to oxidant stress. Hemodialysis is associated with a transient increase in production of reactive oxygen species, particularly with cellulose membranes. In addition, surveys have shown widespread contamination of dialysate by endotoxin, which may cross membranes and prime production of reactive oxygen species by phagocytic cells. Recent studies, however, show a decrease in protein oxidation from pre- to post-dialysis and a normalization of neutrophil reactive oxygen species production. Taken together, these data suggest that uremia, per se, is the most important cause of oxidant stress in hemodialysis patients. Dialysate quality may also contribute to oxidant stress, but evidence that the dialyzer membrane plays a role is weak.

Amino Acid Transport Kinetics and Protein Turnover in Hemodialysis

Background: Protein metabolism is abnormal in patients with end-stage renal disease. However, the etiology of abnormal protein turnover is unclear. Also the role of hemodialysis on protein turnover remains controversial. Abnormal protein metabolism could be due to malnutrition or due to abnormal amino acid transport kinetics Hypothesis: 1) Amino acid transport is abnormal in uremia, 2) Hemodialysis increases fractional protein synthesis rate and c) Net protein accretion is negative during hemodialysis because of increased catabolism. Aim: 1) To study the impact of uremia and hemodialysis on intracellular amino acid transport kinetics and 2) Quantify the fractional protein synthesis rate and degradation in a uremic state and during hemodialysis Methods: Protein turnover and amino acid transport kinetics using stable isotopes of phenylalanine in 2 patients and 2 controls. The patients were placed on a standard diet (1.2 gm/Kg protein and 35 Kcal/Kg) for 2 weeks prior to the study. Acidosis as corrected by NaHCO3 supplementation. Amino acid transport and protein turnover were estimated by compartmental model and precursor product approach respectively. Results: Mean protein intake and HCO3 were 1.4 ± 1 gm/day and 26.8 ± 4.1 meq/L respectively. Inward transport (11.2 ± 2.6 vs. 9.8 ± 2.1 nmol/min−1/100 ml leg−1) and outward transport (10.2 ± 1.2 vs.11.0 ± 1.6 l nmol/min−1/100 ml leg−1) were not different before and during HD. Inward and outward transport in controls were 12.6 ± 3.7 and 16.2 ± 3.5 nmol/min−1/100 ml leg−1 respectively. Protein synthesis was higher than catabolism in the pre-dialysis phase (156.8 ± 66.1 vs. 144.3 ± 53.7 nmol/min/ml leg-1, p = NS), but catabolism was higher than synthesis during HD (172.3 ± 20.5 vs. 186.8 ± 25.8 nmol/min/ml leg-1, p = NS). Protein synthesis and catabolism in controls were 110.8 ± 13.5 and 127.4 ± 12.7 nmol/min/ml leg-1. Conclusion: 1. Inward and outward transport of amino acids are not altered by renal failure or hemodialysis. 2. Protein turnover is increased during hemodialysis, with net balance favoring catabolism

Mutations of mtDNA in renal cell tumours arising in end-stage renal disease.

Toxic effects in the uraemic state or during maintenance dialysis have been suggested to be responsible for DNA damage and tumour development in end-stage renal disease (ESRD). This study therefore analysed the mitochondrial DNA alterations in six kidneys with ESRD and in nine renal cell tumours arising in these kidneys. Sequencing the entire 16 569 bp mitochondrial genome disclosed 94 sequence variations in normal and corresponding tumour tissues. Thirty-eight polymorphisms occurred in the D-loop region, 40 in the polypeptide coding regions, 12 in the rRNAs, and four in the tRNAs. Nine somatic nucleotide changes were found in seven of the nine tumours analysed; four of them were G to A transitions. Two of the G to A changes occurred in the D-loop region, one in the MTTA gene, and one in the MTND2 gene. An A to G substitution was seen in the control region at the mtTF1 binding site. A T to C transition also occurred also in the D-loop region. A T insertion was seen in MTRNR2 (16S rRNA). One C insertion in MTND4 and one A deletion in the polyA tract of the MTND5 gene resulted in frameshift mutations in two tumours. This study reveals a high mutational rate of the mitochondrial DNA in tumours, which may correspond to the increased level of reactive oxidative species in renal parenchymal cells in ESRD.

Cardiovascular effects of successful renal transplantation: a 1-year sequential study of left ventricular morphology and function, and 24-hour blood pressure profile.

Cardiovascular disease is the leading cause of death in renal transplant recipients. The purpose of this study was to determine the effects of a successful renal transplantation on left ventricular morphology and function and on the 24-hr blood pressure profile. Twenty-four patients with end-stage renal disease were prospectively studied by ambulatory blood pressure monitoring and echocardiography before and at 3, 6, and 12 months after renal transplantation. Patients were also analyzed according to their renal function after transplantation. We observed a significant drop in the mean values of daytime and nocturnal systolic blood pressure and in the 24-hr systolic pressure load at 12 months after transplantation. The most frequent echocardiographic finding was left ventricular hypertrophy (LVH), for which the incidence decreased from 75% before transplantation to 52.1% at 12 months after transplantation (P = 0.125). There was a significant decrease in left ventricular dilatation, and systolic dysfunction normalized in all patients after 12 months. The variables that best independently predicted the decrease in LVH were serum creatinine levels and the 24-hr systolic pressure load as registered by ambulatory blood pressure monitoring at 12 months after transplantation. We observed significant decreases in left ventricular mass and left ventricular mass index in the group of patients who had adequate renal function, as compared with no changes in patients who did not. Correction of the uremic state by renal transplantation leads to complete resolution of systolic dysfunction, regression of LVH, and improvement of left ventricular dilatation. In fact the reduction of LVH was dependent on adequate renal function and on a decrease in the systolic pressure levels.

Impact of renal failure on the risk of myocardial infarction and death

It is unclear whether pre-existing cardiovascular disease or predisposition of the uremic state leads to the high cardiovascular morbidity and mortality associated with renal failure. We examined whether renal failure independently increases the risk of myocardial infarction and death. A total of 8600 patients with variable glomerular filtration rate (GFR) at the time of coronary angiography participated in the Intermountain Heart Study. Coronary disease was defined as >or=70% stenosis. Modification of Diet in Renal Disease formula was used to calculate glomerular filtration rate (GFR). Cox regression models were used to compare outcomes. The mean GFR was 71 +/- 24 mL/min. There were 1320 (15%) deaths, 657 (9%) myocardial infarctions and 1776 (21%) death or myocardial infarctions over 3.2 +/- 1.9 years. Compared to the highest GFR quartile, the lowest GFR quartile (mean GFR 41 +/- 14 mL/min) was associated with higher risk for myocardial infarction (RR 1.43, 95% CI 1.15 to 1.78), death (RR 2.77, 95% CI 2.32 to 3.30) and death/myocardial infarction (RR 2.13, 95% CI 1.85 to 2.45) in multivariable models adjusted for age, sex, hypertension, hyperlipidemia, smoking, family history of coronary disease and diabetes. Even after further adjustment for coronary angiographic data and the choice of initial therapy, lowest GFR quartile was associated with increased risk of myocardial infarction (RR 1.51, 95% CI 1.21 to 1.88), death (RR 2.60, 95% CI 2.18 to 3.10) and death/myocardial infarction (RR 2.08, 95% CI 1.80 to 2.39). Even moderate renal failure increases the risk of myocardial infarction and death independent of clinical variables, baseline angiographic evidence of coronary disease and therapy.

Clinical Profiles and Outcomes of End-Stage Renal Failure Patients with Late Initiation of Renal Replacement Therapy Based on Uremic Symptoms under Intensive Renoprotective Therapies

Aim: This study describes the clinical profiles and outcomes of renal failure patients with late initiation of renal replacement therapies (RRT) based on uremic symptoms under intensive treatment prior to the start of RRT (IT). Methods: Thirteen patients (male 10, female 3) with end-stage renal disease who preferred to wait for the initiation of RRT until uremic symptoms appeared regardless of serum creatinine (s-Cr) and 24-hour creatinine clearance (24-hour Ccr) were chosen. All patients received IT including a low-protein diet, antihypertensive drugs including enalapril, erythropoietin and others to prevent and manage uremic states until the initiation of RRT. Clinical findings at the initiation of RRT and the outcomes after the start of RRT were examined. Results: RRT was initiated 23.6 ± 16.9 months after IT without any complication in all patients when mild uremic symptoms appeared. Uremic symptoms, blood pressure, serum albumin, potassium, calcium and urinary Cr excretion were well controlled except inorganic phosphate, hemoglobin and cardiac size. 24-hour Ccr and s-Cr were 3.4 ± 0.7 ml/min and 17.4 ± 3.8 mg/dl at initiation of RRT. The outcomes of all the patients were all well during chronic RRT. Conclusion: Intensive treatment prior to the start of RRT can diminish uremic symptoms and complications so that RRT might be initiated safely and with fewer problems, even in the face of lower 24-hour Ccr and markedly higher s-Cr.

Cardiac effects of chronic inflammation in dialysis patients.

Cardiovascular pathology is the major cause of death in uraemia. There is evidence that a chronic inflammation with activation of C-reactive protein, interleukin-6, tumour necrosis factor-alpha and other cytokines is associated with vascular pathology, both in the general population and in dialysis patients. The cardiovascular system, and particularly the vascular wall, is the main target of the inflammatory process. Inflammation of the coronary arteries could be involved in the development of atherosclerosis and its related clinical syndromes. In the uraemic state, an increased production of pro-inflammatory cytokines may trigger the onset and progression of atherosclerosis and favour the subsequent complications, such as plaque fissuration and rupture. However, inflammatory cytokines also have a depressant action on the myocardium, thus inducing myocardial dysfunction. Together, these conditions may ultimately enhance the risk of myocardial infarction and death. From this standpoint, cardiovascular disease should also be investigated with the traditional biochemical inflammation markers and the evaluation of the circulating cytokine level, although new reliable markers could provide further diagnostic help. New therapeutic approaches should also be considered.

VI.1 Prevention of infection: management of impairment of the host defence

Dysfunction of the host defence is one of the major functional disturbances in end‐stage renal disease [49]. The causes of dysfunction can be divided into two major categories: one caused by the uraemic state itself and the other caused by therapeutic intervention.

Plasma pteridine concentrations in patients with chronic renal failure.

Pteridine metabolism is impaired in the uraemic state. This may affect cardiovascular function and contribute to malnutrition. We wished to clarify further the impact of impaired pteridine metabolism. Using the HPLC method, the plasma concentrations of endogenous pteridines were determined in 64 patients with chronic renal failure (33 on intermittent haemodialysis (HD) treatment vs 31 not yet on renal replacement therapy), and in 18 healthy controls. The patients were classified into three groups on the basis of creatinine clearance (Ccr): group (a), Ccr >60 ml/min; group (b), Ccr=10-60 ml/min; group (c), all patients receiving HD. Total neopterin (NP) and biopterin (BP) levels and the NP/BP ratio (a biomarker for macrophage activity) were significantly higher, whereas tetrahydrobiopterin (BH(4))/dihydrobiopterin (BH(2)) ratio (a biomarker for nitric oxide synthase and phenylalanine hydroxylase activities) was significantly lower in group (c) (118.9+/-11.7 ng/ml, 18.8+/-1.2 ng/ml, 6.79+/-0.53, and 0.26+/-0.06) than in healthy subjects (5.17+/-0.29 ng/ml, 2.83+/-0.19 ng/ml, 1.92+/-0.13, and 1.15+/-0.11; P<0.01). These significant differences were also observed between control and group (b) (12.4+/-2.20 ng/ml, 4.48+/-0.36 ng/ml, 2.81+/-0.48, and 0.74+/-0.08; P<0.01). In groups (a) and (b), significant negative correlations were found between Ccr and the total NP level (r=-0.663, P<0.01), the total BP level (r=-0.492, P<0.01), the BH(2) level (r=-0.677, P<0.01), and the NP/BP ratio (r=-0.493, P<0.01). Conversely, significant positive correlations were found between Ccr and the BH(4)/BH(2) ratio (r=0.602, P<0.01). The reduction of quinoid-type BH(2) to BH(4) is modified in patients with advanced chronic renal failure, before and after the initiation of regular HD treatment. These metabolic alterations may play a role in the impaired macrophage, endothelial constitutive nitric oxide synthase, or phenylalanine hydroxylase (PH) activities observed in such patients.

Bone mineral density and markers of bone turnover in patients with renal transplantation and regular hemodialysis

Background: Decreased bone mineral density (BMD) is a known complication for the uremic state antedating dialysis / renal transplantation (RTx). The issue of stabilized versus continued decrease of BMD especially on long-term basis, continues to be unresolved. Patients and Methods: 
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# hemodialysis (HD-# $
  
%     &'( )&'(-group) had been evaluated for metabolic bone changes by calcium homeostasis parameters (serum calcium, phosphorus, alkaline phosphatase “ALP” and vitamin D “calcitriol”), markers of bone formation (bone alkaline phosphatase “BAP”, osteocalcin “OC”, N-terminal propeptide of collagen type I “PINP”), bone resorption markers (pyridoline “PYL” and deoxypyridoline “DPYL”), and intact parathyroid hormone (iPTH). Also, BMD had been assessed by dual energy x-ray absorptiometry (DEXA) twice, at inclusion time and * !    Results: comparing both groups regarding calcium homeostasis, markers of bone turnover and iPTH showed non significant difference. However, there was a significant drop of BMD (as evidenced by T-score) at follow up in the HD group, compared to stabilization of T-score for the RTx-group. Furthermore, annual T-score change was significantly more in HD-group, compared to RTx-group. Results also showed that, the best marker correlating with T-score annual changes and iPTH to be PINP. Irrespective of normal calcium homeostasis parameters, low BMD is a prevalent disorder among patients on regular HD and renal transplants.Conclusion: Follow up for *! % +, 
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! to continued bone loss in patients on regular HD. This could raise recommendation for calcium and calcitriol supplementation, especially in the predialysis period, early post transplantation period, and continued guided replacement for those on maintenance HD. Serum PINP showed best correlations with BMD changes and iPTH and could be considered a reliable marker reflecting bone formation in those patients.

Bone mineral density and markers of bone turnover in patients with renal transplantation and regular hemodialysis

Background: Decreased bone mineral density (BMD) is a known complication for the uremic state antedating dialysis / renal transplantation (RTx). The issue of stabilized versus continued decrease of BMD especially on long-term basis, continues to be unresolved. Patients and Methods: 
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"#" hemodialysis (HD-#" $
  
 %    " &'( )&'(-group) had been evaluated for metabolic bone changes by calcium homeostasis parameters (serum calcium, phosphorus, alkaline phosphatase “ALP” and vitamin D “calcitriol”), markers of bone formation (bone alkaline phosphatase “BAP”, osteocalcin “OC”, N-terminal propeptide of collagen type I “PINP”), bone resorption markers (pyridoline “PYL” and deoxypyridoline “DPYL”), and intact parathyroid hormone (iPTH). Also, BMD had been assessed by dual energy x-ray absorptiometry (DEXA) twice, at inclusion time and * ! "  " Results: comparing both groups regarding calcium homeostasis, markers of bone turnover and iPTH showed non significant difference. However, there was a significant drop of BMD (as evidenced by T-score) at follow up in the HD group, compared to stabilization of T-score for the RTx-group. Furthermore, annual T-score change was significantly more in HD-group, compared to RTx-group. Results also showed that, the best marker correlating with T-score annual changes and iPTH to be PINP. Irrespective of normal calcium homeostasis parameters, low BMD is a prevalent disorder among patients on regular HD and renal transplants.Conclusion: Follow up for *!" % +, 
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""! to continued bone loss in patients on regular HD. This could raise recommendation for calcium and calcitriol supplementation, especially in the predialysis period, early post transplantation period, and continued guided replacement for those on maintenance HD. Serum PINP showed best correlations with BMD changes and iPTH and could be considered a reliable marker reflecting bone formation in those patients.