Marion G. Koopman

Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate

Creatinine clearance inaccurately estimates true glomerular filtration rate (GFR) because of tubular secretion of creatinine. We studied the ability of oral cimetidine, a blocker of tubular creatinine secretion, to improve the accuracy of measuring creatinine clearance. Clearances of inulin and endogenous creatinine were simultaneously measured in 16 patients with renal disease before administration of cimetidine and during 8 successive 3 h clearance periods with cimetidine 400 mg as priming dose followed by 200 mg every 3 h. At baseline, creatinine relative to inulin clearance (ClC/Cll) ranged from 1.14 to 2.27. With cimetidine, ClC/Cll approached unity in 8 patients (mean 1.02 [SD 0.03]), but considerably exceeded unity in 8 others (1.33 [0.14]). Plasma cimetidine/creatinine ratio was smaller in this second group, due to significantly higher renal clearance of cimetidine (333 [136] vs 165 [89] ml/min, p = 0.01). In a further study, cimetidine dose and, consequently plasma cimetidine concentration, was increased in 6 additional patients who had incomplete inhibited previously. This increased dose completely inhibited tubular creatinine secretion in the third until the sixth hour, so that creatinine clearance equalled GFR. Provided an adequate dose of cimetidine is given, 24 h creatinine clearance during administration of drug measures GFR accurately in patients with renal disease. However, because of the maximum daily dose of cimetidine that is advised, short clearance times (3 h) are recommended.

Damage of the Endothelial Glycocalyx in Dialysis Patients

Damage to the endothelial glycocalyx, which helps maintain vascular homeostasis, heightens the sensitivity of the vasculature to atherogenic stimuli. Patients with renal failure have endothelial dysfunction and increased risk for cardiovascular morbidity and mortality, but the state of the endothelial glycocalyx in these patients is unknown. Here, we used Sidestream Darkfield imaging to detect changes in glycocalyx dimension in dialysis patients and healthy controls from in vivo recordings of the sublingual microcirculation. Dialysis patients had increased perfused boundary region and perfused diameters, consistent with deeper penetration of erythrocytes into glycocalyx, indicating a loss of glycocalyx barrier properties. These patients also had higher serum levels of the glycocalyx constituents hyaluronan and syndecan-1 and increased hyaluronidase activity, suggesting the shedding of these components. Loss of residual renal function had no influence on the imaging parameters but did associate with greater shedding of hyaluronan in blood. Furthermore, patients with higher levels of inflammation had more significant damage to the glycocalyx barrier. In conclusion, these data suggest that dialysis patients have an impaired glycocalyx barrier and shed its constituents into blood, likely contributing to the sustained endothelial cell activation observed in ESRD.

Microbiological quality and quality control of purified water and ultrapure dialysis fluids for online hemodiafiltration in routine clinical practice

During online hemodiafiltration, patients are directly infused with sterile substitution solutions to maintain fluid balance. Adequate water treatment and a well-organized quality control process are essential to provide non-pyrogenic fluids with consistent optimal quality. We sought to assess water quality, the water treatment system, and the methods for surveillance of microbiological water quality in 10 Dutch dialysis centers that routinely treat patients with hemodiafiltration. Microbiological monitoring results (micro-organisms and endotoxins) were collected over a 1-year period representing 11,258 hemodiafiltration sessions covering 97 patients. In all centers, water purification was based on a reverse osmosis module in combination with a second reverse osmosis and/or an electrodeionizer. All centers regularly and routinely monitored the microbiological purity of the dialysis water with adequate analytical methods but with variable monitoring frequency. Microbiological assessments were compliant with reference quality levels in 3923 of 3961 samples. Our study suggests that non-pyrogenic substitution fluids can be produced online for a prolonged period of time. It is likely that the current Dutch Quality of Care Guideline has contributed to high-quality water treatment and a well-organized control process.

Nonpharmacological Lipoprotein Apheresis Reduces Arterial Inflammation in Familial Hypercholesterolemia

BACKGROUND Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk. OBJECTIVES This study used (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients. METHODS In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed. RESULTS In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (β = 0.001; p = 0.02) and atherosclerosis risk factors (β = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02). CONCLUSIONS The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B-containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins.

Blood Pressure Response to Uncomplicated Hemodialysis: The Importance of Changes in Stroke Volume

Background: The cause of blood pressure (BP) changes during uncomplicated hemodialysis (HD) has not been fully investigated. Controversy exists whether changes in BP result from changes in stroke volume (SV) or total peripheral resistance (TPR). Methods: We investigated 19 patients using continuous BP monitoring (Portapres®) and subsequent Modelflow® analysis, yielding continuous SV, cardiac output (CO) and TPR values. Blood volume (BV) monitoring was also performed. For each patient, the sensitivity index (SI) was calculated. The SI is the slope of the curve depicting the relationship between the systolic BP (SBP) response and the BV response. The patients were divided into two groups: group A had an SI >1 which means a decrease in SBP in response to BV change, and group B had an SI <1. In these patients, SBP remained stable despite a BV change. Results: Baseline characteristics and baseline values of all parameters were similar between the groups. In group A, SBP decreased by 25 ± 19 mm Hg and in group B the SBP increased by 5.0 ± 29 mm Hg (p < 0.05), while BV change was similar (10.6 ± 4.9 and 11.2 ± 4.2%, respectively). The difference in SBP response was caused by a different SV response (group A –44 ± 16% and group B –26 ± 18%, p = 0.04), while the TPR response was similar (71 ± 27% in group A vs. 59 ± 58% in group B). Conclusion: Patients responding with a BP decrease to BV reduction during uncomplicated HD differ in their SV response from patients with a stable BP.

Circadian variation of urinary albumin excretion in pregnancy

Objective The hypothesis was tested that circadian variations in urinary albumin excretion of pregnant women in the third trimester of normal pregnancy are different from nonpregnant individuals.

Atorvastatin and the dyslipidemia of early renal failure

Information about lipid abnormalities and the effect of lipid lowering therapy in the early stage of renal disease is limited, while preventive treatment in this stage might be much more beneficial. Lipid profiles and risk factors were assessed in 150 consecutive, non-diabetic patients. Preventive therapy consisted of cholesterol-reduced diet and atorvastatin 10 mg daily. Patients were considered at risk for cardiovascular disease if LDL-cholesterol was >2.6 mmol/l in the case of manifest cardiovascular disease (n=28) or when they had manifest cardiovascular risk factors (n=105) or if LDL was >3.5 mmol/l (n=17). A total of 128 patients (85%) had increased LDL. In men <60 years and women <40 years, total cholesterol was higher than in the general population. Linear regression analysis showed a decreased creatinine clearance to be significantly associated with the lipid profile. For a 10 ml/min decrease of creatinine clearance, a 0.085 increase of the total cholesterol to HDL ratio was observed (P=0.005). In similar analyses, proteinuria was strongly associated with cholesterol and triglycerides. An increase of 0.28 of the total cholesterol/HDL ratio was observed for each gram per 24 h proteinuria (P<0.001). On atorvastatin 10 mg daily, 30 of 60 treated patients had achieved their target LDL value. On average, LDL-cholesterol was reduced by 39% and triglycerides by 18%. No patient had to interrupt their treatment because of adverse side-effects. In conclusion, the majority of patients had an elevated LDL and other lipid abnormalities. Short-term therapy with atorvastatin and a cholesterol lowering diet appears to be safe and effective. It is probably useful to determine the lipid profile in patients with renal failure already in an early phase and to start lipid lowering treatment as soon as abnormalities are found.

The dyslipidemia of chronic renal disease: effects of statin therapy.

Purpose of review Dyslipidemia is a prevalent condition in patients with chronic renal disease, but is often left untreated. Statin treatment constitutes an effective way to improve lipid abnormalities. This review summarizes present studies on dyslipidemia and its treatment in patients with chronic renal disease. Recent findings The specific dyslipidemia in renal disease is associated with the presence of proteinuria and decreased creatinine clearance, and may even adversely affect the progression of chronic renal disease. Statin therapy may have renoprotective effects due to a combination of lipid lowering and pleiotropic effects. Statins exert several anti-inflammatory properties and lead to a decrease of proteinuria. Post-hoc analyses of large-scale lipid lowering trials have shown that the reduction of cardiovascular risk was equivalent to the reduction achieved in patients without chronic renal failure. We feel, however, that if intervention with statins is postponed until patients reach end-stage renal disease, statins have limited benefit. Summary Present studies suggest that patients with renal disease should be screened early for dyslipidemia and that statins have to be considered as the lipid lowering therapy of choice. These drugs reduce cardiovascular risk. Further studies are needed to firmly establish whether statins preserve renal function.

Monocyte-induced increase in osmotic fragility of human red cells sensitized with anti-D alloantibodies.

The mechanism by which human monocytes increase the osmotic fragility of red cells sensitized with Rhesus alloantibodies anti‐D was studied in vitro. Both the increase in osmotic fragility and the lysis of red cells by monocytes were enhanced by cytochalasin B and were inhibited by hydrocortisone. These effects were similar to the effects of these agents on lysosomal enzyme release by monocytes. However, hydrocortisone was completely ineffective when added I h after mixing monocytes and sensitized red cells. This indicates that the damage responsible for the fragility increase and lysis is completed within I h and suggests that it is due to lysosomal enzymes released by the monocytes. Since for the full expression of the osmotic fragility increase and lysis an incubation time much longer than I h is required, it appears that the latter phenomena are the non‐specific sequelae of damage inflicted upon the red cell by released lysosomal enzymes.

Poor compliance with guidelines on anemia treatment in a cohort of chronic hemodialysis patients

Background/Aims: Guidelines for the management of anemia and iron deficiency in chronic hemodialysis (HD) patients have been developed to standardize therapy and improve clinical outcome. The present study evaluated compliance with anemia guidelines and investigated whether differences between centers were present. Methods: Data on anemia management from patients in the baseline cohort of the CONTRAST study (NCT00205556) were analyzed. 598 chronic HD patients (62% male, age 63.6 ± 14.0 years) from 26 Dutch dialysis centers were included. Results: Mean hemoglobin (Hb) level was 11.9 ± 1.3 g/dl and Hb was ≥11.0 g/dl in 81% of the patients. Compliance with all anemia targets (Hb 11.0–12.0 g/dl, transferrin saturation ratio ≥20%, ferritin 100–500 ng/ml) was reached in 11.6% (95% CI 7.8–17.0) of the patients, with a wide range among centers (4–26%, adjusted for case mix, treatment-related factors and center-specific characteristics). Conclusion: Compliance with anemia targets in stable HD patients was poor and showed a wide variation between treatment facilities.