Norbert Lameire

Endothelial dysfunction in diabetes

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium‐derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium‐derived hyperpolarizing factor (EDHF). Impaired endothelium‐dependent vasodilation has been demonstrated in various vascular beds of different animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium‐derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia‐induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non‐enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium‐dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to differ according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.

Contrast-Induced Nephropathy A Clinical and Evidence-Based Approach

Contrast medium–induced nephropathy (CIN) is a common cause of acute renal dysfunction. During the past few years, several publications have provided clinical and experimental data on this topic. Our review focuses on 4 major concerns of CIN relevant in clinical practice: (1) What is the evidence that CIN is a clinically relevant and a dangerous condition for the patient? (2) Is there a difference in CIN rate among different contrast media, and how is that related to the physicochemical properties of different available contrast media? (3) What is the evidence that periprocedural hydration is an effective, appropriate, and safe method to prevent CIN? (4) What is the evidence for the use of a drug, in particular acetylcysteine, to prevent CIN?nnCIN has gained increased attention in the clinical setting, particularly during cardiac intervention but also in many other radiological procedures in which iodinated contrast media are used. There is at present good clinical evidence from well-controlled randomized studies that CIN is a common cause of acute renal dysfunction.1,2 CIN is the acute deterioration of renal function after parenteral administration of radiocontrast media in the absence of other causes. CIN is generally defined as an increase in serum creatinine concentration of >0.5 mg/dL (>44 μmol/L) or 25% above baseline within 48 hours after contrast administration.3–7nnAlthough the exact mechanisms of CIN have yet to be fully elucidated, several causes have been described. Increased adenosine-, endothelin-, and free radical–induced vasoconstriction and reduced nitric oxide– and prostaglandin-induced vasodilatation have been observed. These mechanisms cause ischemia in the deeper portion of the outer medulla, an area with high oxygen requirements and remote from the vasa recta supplying the renal medulla with blood. Contrast agents also have direct toxic effects on renal tubular cells, causing vacuolization, altered mitochondrial function, and apoptosis.8 Atopy …

The changing epidemiology of acute renal failure

Different definitions of acute renal failure (ARF) abound. The existence of multiple definitions makes it difficult to determine the true epidemiological characteristics of this condition. Despite this difficulty, it has been possible to detect notable variations in the epidemiology of ARF during the past few decades. The absolute incidence of ARF has increased, while associated mortality rate has remained relatively static. Several factors have contributed to this altered epidemiology. Here, we discuss the relative contribution of these factors, which include site of disease onset (developed or developing countries, community or hospital or intensive care unit), patient age, infections (HIV, malaria, leptospirosis and hantavirus), concomitant illnesses (cardiopulmonary failure, hemato-oncological disease), and interventions (hematopoietic progenitor cell and solid organ transplantation).

Peripheral Arterial Disease in Patients With End-Stage Renal Disease Observations From the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Background— Patients with end-stage renal disease are at high risk for cardiovascular morbidity and mortality. The aims of the present study were to describe the prevalence of peripheral arterial disease (PAD) and its effects on prognosis and health-related quality of life (HRQOL) in an international cohort of patients on hemodialysis. Methods and Results— Data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective, international, observational study of hemodialysis patients (n=29 873), were analyzed. Associations between baseline clinical variables and PAD were evaluated by logistic regression analysis. Cox regression models were used to test the association between PAD and risk for all-cause mortality, cardiac mortality, and hospitalization. PAD was diagnosed in 7411 patients (25.3%) with significant geographic variation. Traditional cardiovascular risk factors including age, male sex, diabetes, hypertension, and smoking were identified, together with the duration of hemodialysis, as significant correlates of PAD. Diagnosis of PAD was associated with increased all-cause mortality (hazard ratio [HR]=1.36; P<0.0001), cardiac mortality (HR=1.43; P<0.0001), all-cause hospitalization (HR=1.19; P<0.0001), and hospitalization for a major adverse cardiovascular event (HR=2.05; P<0.0001). HRQOL questionnaires revealed physical health scores that were significantly lower in PAD compared with non-PAD patients (P<0.0001). Conclusions— PAD is common in hemodialysis patients and is associated with increased risk of cardiovascular mortality, morbidity, and hospitalization and reduced HRQOL.

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin – induced diabetic rats is restored by 5-methyltetrahydrofolate

Aims/hypothesis. Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiology of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease. Methods. Endothelium-dependent and endothelium-independent vasodilator responses were investigated in the renal microcirculation of streptozotocin-induced diabetic rats. We measured renal blood flow changes with an electromagnetic flow probe. In addition, the responses of the different segments of the renal microcirculation were evaluated with videomicroscopy using the hydronephrotic kidney technique. Because endothelial cells release different relaxing factors (nitric oxide, prostacyclin and an unidentified endothelium-derived hyperpolarizing factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor l-NG-nitroarginine methylester HCI (l-NAME) and the cyclooxygenase inhibitor indomethacin. We evaluated with the effect of 5-methyltetrahydrofolate, the active form of folate, on the responses. Results. The l-NAME- and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with control rats, suggesting impaired endothelium-derived hyperpolarizing factor-mediated vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate) and to the K+-channel opener pinacidil were similar in diabetics and controls, indicating intact endothelium-independent vasodilator mechanisms. The contribution of endothelium-derived hyperpolarizing factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabetic rats, the response to acetylcholine was increasingly impared as vessel size decreased. Defective vasodilation in diabetic kidneys was rapidly normalized by 5-methyltetrahydrofolate. Conclusion-interpretation. Endothelium-derived hyperpolarizing factor-mediated vasodilation is impaired in the renal microcirculation of diabetic rats, in particular in the smallest arteries. Treatment with folate restores the impaired endothelial function in diabetes. [Diabetologia (2000) 43: 1116–1125]

Reimbursement of Dialysis: A Comparison of Seven Countries

Reimbursement for chronic dialysis consumes a substantial portion of healthcare costs for a relatively small proportion of the total population. Each country has a unique reimbursement system that attempts to control rising costs. Thus, comparing the reimbursement systems between countries might be helpful to find solutions to minimize costs to society without jeopardizing quality of treatment and outcomes. We conducted a survey of seven countries to compare crude reimbursement for various dialysis modalities and evaluated additional factors, such as inclusion of drugs or physician payments in the reimbursement package, adjustment in rates for specific patient subgroups, and pay for performance therapeutic thresholds. The comparison examines the United States, the province of Ontario in Canada, and five European countries (Belgium, France, Germany, The Netherlands, and the United Kingdom). Important differences between countries exist, resulting in as much as a 3.3-fold difference between highest and lowest reimbursement rates for chronic hemodialysis. Differences persist even when our data were adjusted for per capita gross domestic product. Reimbursement for peritoneal dialysis is lower in most countries except Germany and the United States. The United Kingdom is the only country that has implemented an incentive if patients use an arteriovenous fistula. Although home hemodialysis (prolonged or daily dialysis) allows greater flexibility and better patient outcomes, reimbursement is only incentivized in The Netherlands. Unfortunately, it is not yet clear that such differences save money or improve quality of care. Future research should focus on directly testing both outcomes.

How to use biomarkers efficiently in acute kidney injury

We discuss the performance of novel biomarkers in acute kidney injury (AKI). Comparison of the areas under the receiver operating characteristic curves of several biomarkers with some clinical and/or routine biochemical outcome parameters reveals that none of the biomarkers has demonstrated a clear additional value beyond the traditional approach in clinical decision making in patients with AKI. Unscrutinized use of these biomarkers may distract from adequate clinical evaluation and carries the risk of worse instead of better patient outcome.

Fractionation of vanadium complexes in serum, packed cells and tissues of Wistar rats by means of gel filtration and anion-exchange chromatography

Abstract. Male Wistar rats were intraperitoneally injected with [48V]vanadium tracer to (1) investigate the distribution of vanadium over different tissues and (2) study the distribution of vanadium over the proteins and peptides in serum, packed cells and homogenates of tissues by means of liquid chromatography experiments (size exclusion, ion exchange). Target organs were primarily kidney, bone, spleen and liver. In serum we found that vanadium was mainly bound to transferrin; however, a small amount was also bound to albumin. Besides these two complexes, a significant part of vanadium occurred as readily exchangeable (free) vanadium. In packed cells, vanadium is mainly bound to hemoglobin and to two abundant low molecular mass complexes. The chromatograms of tissues (kidney, liver, testes, spleen and lung) show similar high molecular mass complexes (vanadium co-elutes with ferritin, transferrin and hemoglobin). Between the low molecular mass complexes there are similar peaks for spleen, testes and kidneys on the one hand, and liver and lung on the other hand, albeit the differences are small. In the case of lung, there is an additional low molecular mass peak.

C-Reactive Protein and Mortality in Hemodialysis Patients: The Dialysis Outcomes and Practice Patterns Study (DOPPS)

Background: We examined associations of C-reactive protein (CRP) levels with mortality in Japanese hemodialysis patients and trends in prevalence of CRP measurement at hemodialysis facilities internationally. To assess whether measurement of CRP may influence outcomes, we examined associations of facility prevalence of CRP measurement with mortality. Methods: CRP measurements were from a cross-section of patients in the international Dialysis Outcomes and Practice Patterns Study (n = 610 facilities, 16,355 patients). Cox proportional hazards models assessed associations of mortality with CRP in Japan, and with a facility’s frequency of measuring CRP internationally, (except in the USA and Canada). Results: From 2002–2004, CRP was measured in 0–19% of patients in each country, except Japan (55%). From 2005–2007, CRP was measured in ≧50% of country patients except in Canada (15%) and the USA (2%). After multivariable adjustment, the hazard ratio (HR) of death was 1.6- to 2.4-fold higher (p < 0.05) for various categories of CRP levels >3 mg/l (vs. <1.0 mg/l). Cardiovascular mortality risk was lower in facilities measuring CRP for ≧50% of patients (HR = 0.72, p = 0.01) in multivariable-adjusted analyses. Conclusions: CRP is informative regarding mortality risk beyond that provided by other inflammatory and nutritional markers, with significantly higher risk seen at CRP >3 mg/l. Greater use of CRP may lead to improved patient care as suggested by the association of greater CRP measurement with lower cardiovascular mortality.

Pathophysiological role of vascular endothelial growth factor in the remnant kidney.

Background: Subtotal renal ablation is characterized by initial glomerular hypertrophy, followed by progressive development of glomerulosclerosis and interstitial fibrosis. Vascular endothelial growth factor (VEGF) is involved in glomerular hypertrophy and dysfunction in several pathophysiological conditions. On the other hand, progressive glomerulosclerosis and tubulo-interstitial fibrosis in the remnant kidney have been associated with loss of VEGF expression. Methods: To explore the pathophysiological role of VEGF in the development of glomerular hypertrophy and renal damage in the remnant kidney model, we examined the effect of a neutralizing VEGF antibody on glomerular volume and kidney function in rats after subtotal nephrectomy or sham operation. Erythropoietin was administered to exclude a confounding effect of anaemia. Results: Six weeks after subtotal nephrectomy, plasma urea and creatinine concentrations, urinary albumin excretion, and mean glomerular volume were elevated in the placebo-treated uraemic rats as compared with the sham-operated rats. Inhibition of VEGF partially prevented the glomerular hypertrophy and largely prevented the rise in urinary albumin excretion, but did not affect creatinine clearance in uraemic rats. Conclusions: VEGF is a mediator of glomerular hypertrophy after subtotal renal ablation. In view of glomerular hypertrophy as the initial deleterious event ultimately leading to progressive glomerulosclerosis, agents that block this glomerular growth could be useful in preventing scarring in progressive renal disease.