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The concentration of plasma creatinine and the estimated glomerular filtration rate, calculated from plasma creatinine, age, weight, and gender, are used to assess kidney function. In routine clinical practice the concentration of plasma urea is often determined at the same time as the creatinine concentration. Urea is a waste product of the breakdown of amino acids and is excreted by the kidneys. Thus reduced kidney function results in a rise of blood urea. In addition, the urea concentration is determined by protein supply and catabolism. The sensitivity and specificity of urea in the diagnosis of kidney dysfunction are therefore low. In only a limited number of cases might measuring urea be helpful in determining the cause of reduced kidney function.

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BACKGROUND: Chronic kidney disease (CKD) is defined as the presence of kidney damage, albuminuria or a reduction in glomerular filtration rate (GFR). A GFR <60 mL/min/1.73 m(2) alone is sufficient to diagnose CKD Stages III-V. Recently, the new chronic kidney disease epidemiology collaboration (CKD-EPI) equation was introduced. It has been suggested to result in higher estimated glomerular filtration rates (eGFRs) than the Modification of Diet in Renal Disease (MDRD(4)) formula. Here, we assess consequences of introducing the CKD-EPI equation in a West European Caucasian population. METHODS: Data were obtained from 6097 Caucasian participants of the Nijmegen Biomedical Study (2823 males and 3274 females). Serum creatinine values were determined using the Jaffe method, calibrated against mass spectrometry and were used to calculate eGFR(MDRD4) and eGFR(CKD-EPI). Demographic data, health status and information on medication use for all participants was obtained with a postal questionnaire. RESULTS: The introduction of the CKD-EPI equation changed the curve of eGFR by age, with higher values in the younger age groups and a steeper decline of eGFR with ageing. As a consequence, younger people were more often classified to a higher GFR stage and older people, especially males, to a lower GFR stage. CONCLUSIONS: In comparison with the MDRD(4) formula, the CKD-EPI equation leads to higher estimates of GFR in young people and lower estimates in the elderly. On a population level, this may lead to higher estimates of kidney function. However, in routine clinical practice where the population is predominantly elderly, the opposite may be true. The introduction of eGFR(CKD-EPI) necessitates reconsidering the definition of CKD. We suggest introducing age-dependent threshold values and/or the use of urinary albumin excretion to improve risk stratification.

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BACKGROUND: An accurate prediction of prognosis in patients with idiopathic membranous nephropathy (iMN) would allow restriction of immunosuppressive treatment to patients who are at highest risk for end-stage renal disease (ESRD). Several markers of proximal tubular cell injury have been used as predictors of prognosis. In this study we compared the accuracy of urinary beta-2-microglobulin (U beta 2m) and N-acetyl-beta-glucosaminidase (U beta-NAG) in predicting renal insufficiency and remission rates. METHODS: Fifty-seven patients with iMN (38 M, 19 F; age 48 +/- 16 years), a nephrotic syndrome and a serum creatinine level <135 micromol/l were studied prospectively. At baseline, a standardised measurement was carried out to determine renal function and protein excretion. The end-point renal failure was defined as a serum creatinine exceeding 135 micromol/l or an increase in serum creatinine by >50%. Remission was defined as a proteinuria <2.0 g/day with stable renal function. RESULTS: The mean follow-up was 80 +/- 36 months. The mean serum creatinine concentration was 89 +/- 20 micromol/l, serum albumin 24 +/- 5.3 g/l and proteinuria 8.9 +/- 4.8 g/24 h. Thus far, 28 (49%) patients have reached the predefined end point of renal failure. Multivariate analysis identified U beta 2m as the strongest independent predictor for the development of renal insufficiency. Sensitivity and specificity were 81 and 90% respectively for U beta 2m (threshold value 54 microg/mmol cr), and 74 and 81% respectively for U beta-NAG (threshold value 2.64 U/mmol cr). The overall remission rate was 44%. A remission occurred in 78% of patients with low U beta 2m and in 14% of patients with high U beta 2m, and respectively in 71% of patients with low U beta-NAG and 21% of patients with high U beta-NAG. CONCLUSIONS: Although both U beta 2m and U beta-NAG predicted progression and remission in iMN, U beta 2m was more accurate. High specificity in predicting prognosis should be pursued to avoid unnecessary immunosuppressive therapy. We therefore conclude that U beta 2m is superior to U beta-NAG in predicting prognosis in patients with iMN.

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Although iron is essential for living organisms to survive, its reactive properties require strict regulation in order to prevent toxic effects. Hepcidin, a liver produced peptide hormone, is thought to be the central regulator of body iron metabolism. Its production is mainly controlled by the erythropoietic activity of the bone-marrow, the amount of circulating and stored body iron, and inflammation. Recent reports, however, provide new hypotheses on how hepcidin might exert its regulatory function. Although hepcidin was first discovered in human urine and serum, most of our understanding of hepcidin regulation and action comes from in vitro and mice studies that often use hepcidin mRNA expression as a read out. The difficulties in carrying out studies in humans have mostly been due to the lack of suitable hepcidin assay. The recent development of assays to measure hepcidin in serum and urine has offered new opportunities to study hepcidin regulation in humans. However, for the moment, only a small number of laboratories are able to perform these assays. The aim of this review is to discuss insights into hepcidin regulation obtained from recent clinical studies in the light of findings from in vitro and mice studies. Ongoing studies in humans should provide us with more information on the etiology of iron metabolism disorders in order to create new therapeutic strategies and improve differential diagnosis protocols for these diseases.

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OBJECTIVES: Differences in peritoneal fluid handling in the acute setting can be expected if children are converted to pH-neutral dialysis solutions because conventional acidic solutions exert toxic effects on peritoneal mesothelial cells and microcirculation. Peritoneal fluid kinetics was therefore investigated with both types of solutions in a group of children. DESIGN: Peritoneal equilibration tests (PETs) were performed in 12 patients [mean age 70 months, mean time on peritoneal dialysis (PD) 18 months] using a pH-neutral PD fluid (Physioneal 3.86%; Baxter Ltd, Castlebar, Ireland) and dextran 70 as a volume marker. The results of these PETs were compared to those of a historic group of 12 children (mean age 75 months, mean time on PD 17 months). SETTING: Pediatric dialysis unit in a tertiary institute. PATIENTS: Stable pediatric PD patients. MAIN OUTCOME MEASURES: Transcapillary ultrafiltration (TCUF) and marker clearance, dialysate-to-plasma (D/P) ratios for urea and creatinine, and D(t)/D(0) ratio for glucose. RESULTS: TCUF and lymphatic absorption were not different between the two groups. There was also no significant difference in small solute clearance measured by D/P ratio for urea and creatinine and D(t)/D(0) ratio for glucose. CONCLUSION: Peritoneal fluid kinetics is not significantly altered if pH-neutral dialysis solutions are applied compared to acidic solutions. An altered TCUF, as is hypothetically possible using an acidic solution, was not established.

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The human bowel contains a large and dynamic bacterial population that is not only essential for intestinal health, but also critical for the development of diseases such as cancer. In this respect, the Gram-positive bacterium Streptococcus bovis has been associated with colon cancer for many years. To investigate the clinical importance of this association, an immunocapture mass spectrometry assay was developed that can generate infection-related protein profiles. The composition of these profiles is governed by the capture of specific antigens by serum antibodies from colon cancer patients. This assay showed that S. bovis antigen profiles could distinguish 11 out of 12 colon cancer patients from 8 control subjects, whereas antigen profiles derived from the gut bacterium Escherichia coli were not diagnostic for colon cancer. Moreover, S. bovis antigen profiles were also detected in polyp patients, indicating that infection with this bacterium does occur early during carcinogenesis. Highly accurate tandem mass spectrometry was used to identify one of the diagnostic antigens as a surface-exposed heparin-binding protein, which might be involved in attachment of S. bovis to tumor cells. Together, these findings corroborate the hypothesis that colonic lesions provide a specific niche for S. bovis, resulting in tumor-associated "silent" infections. These infections, however, only become apparent in colon cancer patients with a compromised immune system (bacteremia) or coincidental cardiac valve lesions (endocarditis). This makes profiling of the humoral immune response against "silent" S. bovis infections a promising diagnostic tool for the early detection of human colon cancer, which is crucial for the effective treatment of this disease.

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OBJECTIVES: The differentiation of white blood cells is a worldwide-accepted method to obtain medical information. The conventional microscopic differential, however, is a laborious and expensive test with a low statistical value. Especially for band cell identification there is a wide range of variance. In this report we describe the intervariability of band cell enumeration. METHODS: From a septic patient, an EDTA anti-coagulated blood sample was obtained and a smear was made and stained (May-Grünwald Giemsa). A PowerPoint presentation was made twice of 100 random cells and sent to 157 different hospital laboratories in the Netherlands for a leukocyte differential. In the first survey neutrophils were differentiated in segmented and band neutrophils whereas in the second survey no discrimination was made between segmented and band neutrophils. RESULTS: The first survey was responded by 68% of the laboratories (756 individuals) and the second survey by 73% of the laboratories (637 individuals). The laboratory mean values of the segmented neutrophils were 42.9% (SD: 7.8, range 22-64%) and 69.9% (SD: 1.4, range 62-72%) for the first and second survey respectively. For the individual technicians the values of the segmented neutrophils were 43.9% (SD: 11.2, range 15-72%) and 70.0% (SD: 2.0, range 59-77%) for the first and second survey respectively. CONCLUSIONS: Because of the enormous variation of band cell counting we recommend to cease quantitative reporting of band cells, especially since the results only have a clinical relevance in a limited number of pathological circumstances.

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The hepatic peptide hormone hepcidin is the central regulator of iron metabolism and mediator of anemia of inflammation. To date, only one specific immuno-dot assay to measure hepcidin in urine had been documented. Here we report an alternative approach for quantification of hepcidin in urine by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Peptide peaks were detected corresponding to the 3 forms of hepcidin normally found in urine. The identity of the peptide peak equivalent to hepcidin-25 was confirmed using synthetic human hepcidin-25. Validation of our MS data on samples with various hepcidin levels showed a strong correlation with previous immuno-dot assay results (Spearman R = 0.9275, P < .001). Most importantly, this hepcidin assay clearly discriminates between relevant clinical iron disorders. In conclusion, this novel MS urine hepcidin assay is easy to perform and available to a wide audience. This enables the implementation of hepcidin measurements in large clinical studies.

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Sodium sieving is a consequence of dissociation between the amount of water and sodium transported over the peritoneal membrane. This dissociation occurs in the presence of aquaporin-mediated water transport. Sieving of sodium can be used as a rough measure for aquaporin-mediated water transport. Icodextrin contains glucose polymers, inducing ultrafiltration by colloid osmosis. Therefore, aquaporins play a minor role in ultrafiltration, which is confirmed by the absence of sodium sieving. Icodextrin is very suitable for the daytime dwell in children on a nightly intermittent peritoneal dialysis regimen. Ultrafiltration obtained with icodextrin is similar to ultrafiltration obtained with 3.86% glucose after a 12-hour dwell. When using icodextrin in children, it is also confirmed by the absence of sodium sieving that the aquaporins play a minor role in ultrafiltration.

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OBJECTIVES: To establish intraperitoneal pressure (IPP) in a relatively large pediatric study group and to study the effects of a 3.86% glucose solution and a 7.5% icodextrin solution on IPP during a 4-hour dwell. DESIGN: IPP was measured with the patient in a supine position. The intraperitoneal volume (IPV) was 1200 mL/m2 with a 1.36% glucose solution. The influence of dialysis solutions was obtained by performing two 4-hour peritoneal equilibration tests (PETs) with 3.86% glucose and 7.5% icodextrin as test solution, using an IPV of 1200 mL/m2 and dextran 70 as volume marker. IPP was measured at two consecutive time points (t = 0 and t = 240 minutes). Transcapillary ultrafiltration, net ultrafiltration, and marker clearance were calculated. PATIENTS: IPP was established in 30 patients with median age of 4.5 years (range 1.0 - 14.9 years). Influence of dialysis solutions on IPP was studied in 9 children with median age of 4.2 years (range 1.7 - 10.9 years) and median treatment period of 12 months (range 5.6 - 122.3 months). RESULTS: Mean IPP was 12.0 +/- 6.5 cm H2O. Significant relations were found between the change in IPP and transcapillary ultrafiltration and body surface area during the PET with 3.86% glucose. No relations were seen during the PET with icodextrin. CONCLUSIONS: IPP was established in a large pediatric study group and was similar to previously published values of IPP in a small number of patients. Differences in fluid kinetics have different effects on the change in IPP during a 4-hour dwell period.

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Scarce data are available on the use of glucose polymer-based dialysate in children. The effects of glucose polymer-based dialysate on peritoneal fluid kinetics and solute transport were studied in pediatric patients who were on chronic peritoneal dialysis, and a comparison was made with previously published results in adult patients. In nine children, two peritoneal equilibration tests were performed using 3.86% glucose and 7.5% icodextrin as a test solution. Dextran 70 was added as a volume marker to calculate fluid kinetics. Serum and dialysate samples were taken for determination of urea, creatinine, and sodium. After calculation of the initial transcapillary ultrafiltration (TCUF) rate, it was possible to calculate the contribution of aquaporin-mediated (AQP-mediated) water transport to ultrafiltration for icodextrin and 3.86% glucose and the part of L(p)S (the product of the peritoneal surface area and the hydraulic permeability) caused by AQP. In children, the transport parameters were similar for the two solutions, except for TCUF, which was lower for icodextrin (0.9 ml/min per 1.73 m(2)) as compared with 3.86% glucose (4 ml/min per 1.73 m(2)). Transport parameters were similar in children and adults for glucose, but with icodextrin, TCUF and marker clearance were significantly lower in children. AQP-mediated water flow was 83 versus 50% with glucose (child versus adult; P < 0.01) and 18 versus 7% with icodextrin (P < 0.01). Data indicate that transport parameters in children using icodextrin are similar to glucose except for TCUF. Differences are explained by the absence of crystalloid osmosis and that TCUF was determined after a 4-h dwell. Comparison of transport parameters and peritoneal membrane characteristics between children and adults reveal that there seem to be differences in the amount and functionality of AQP. However, there are no differences in clinical efficacy of this transport pathway because the absolute flow through the AQP is identical in both groups using 3.86% glucose.

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BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) used in antiretroviral therapy may cause mitochondrial toxicity. Mitochondrial dysfunction leads to disturbance of the glucose metabolism, resulting in an accumulation of L-lactate (L) and pyruvate (P), with an enhanced L/P ratio. OBJECTIVES: We analysed lactate and pyruvate blood samples of patients of our outpatient department. Aim of the analysis was to detect preliminary mitochondrial toxicity in patients on antiretroviral nucleoside analogues, which might result in disturbances of L, P, L/P ratio, bicarbonate (Bic) or beta-hydroxybutyrate/aceto-acetate (beta-HB/AA) ratios. STUDY DESIGN: Blood samples of L, P, Bic, beta-HB and AA were analysed in four groups of subjects. The first group (A) consisted of patients with presumed NRTI-related adverse events (n=21), the second group (B) consisted of patients without adverse events (n=28), the third group (C) were HIV-infected patients without antiretroviral therapy (n=6) and the last group (D) were healthy controls (n=12). The mean duration of NRTI-treatment was 18 months (range 0-78 months). RESULTS: The mean lactate level in group A was 2319 micromol/l (S.D. +/-1231, median 1741 micromol/l), in group B 1257 micromol/l (S.D. +/-607, median 1087), Group C 1285 (S.D. +/-451, median 1245 micromol/l) and 951 micromol/l (S.D. +/-270, median 979) in the healthy controls. No significant differences in pyruvate, L/P, Bic and beta-HB/AA were seen in the four groups. The mean lactate level in patients on stavudine was 1980 micromol/l (S.D. +/-1197) versus 1051 micromol/l (S.D. +/-395, P=0.01) in patients on zidovudine. All patients with lactate values above 2700 micromol/l (eight) experienced adverse events. CONCLUSION: Lactate levels were higher in patients with presumed NRTI-related adverse events. Furthermore, HIV patients receiving a stavudine containing antiretroviral therapy had higher lactate values than patients without stavudine. Although routine lactate measurement in all patients on antiretroviral therapy is not recommended, lactate measurement might be useful for follow up of patients with presumed NRTI-related adverse events and in patients with lactate levels above 2500 micromol/l. These patients require extra surveillance to evaluate if discontinuation of the current antiretroviral therapy is needed.

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BACKGROUND: We evaluated a quality control scheme for the measurement of urinary uroporphyrin, coproporphyrin, total urinary porphyrins and precursors of urinary porphyrins, delta-aminolevulinic acid and porphobilinogen that was performed in The Netherlands during a period of 5 years. METHODS: Six quality control samples were distributed each year to the participating laboratories. Mean concentrations and the corresponding coefficients of variation were calculated. RESULTS: Coefficients of variation varied widely and were very high in the concentration ranges that can be found in patients with low-grade porphyria. CONCLUSION: Commutable calibrators are needed to improve the laboratory diagnosis of porphyria.

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The European Communities Confederation of Clinical Chemistry and Laboratory Medicine (EC4) opened a Register for European Chemists in 1997. The operation of the Register is undertaken by a Register Committee (EC4RC). During the last 5 years more than 1,400 clinical chemists entered the register. In this article an update of the first Guide to the Register is given, based on the experience of 5 years of operation and the development of the discipline. The registration is valid for 5 years. In a second part the procedure and the conditions for re-registration are presented.

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BACKGROUND: It has been suggested that serum cystatin C (cyst-C) concentration provides a better indication of changes in glomerular filtration rate (GFR) than does serum creatinine concentration. METHODS: Because of conflicting results as to the usefulness of cyst-C, we compared the GFRs calculated from serum cyst-C, inulin clearance and endogenous creatinine clearance in children. GFRs calculated from cystatin concentration, inulin clearance following a single injection and endogenous creatinine clearance using Jaffé and enzymic methods were compared in 66 children (1.3-21.9 years) with a variety of renal disorders. Receiver operating curve analysis was used to determine the cut-off value that would give the best discrimination between normal and decreased GFR. RESULTS: The serum cyst-C concentration ranged from 0.66 to 7.61 mg/L (median 1.94). Serum creatinine Jaffé concentration (creat-J) ranged from 38 to 871 micro mol/L (median 105) and creatinine enzymatic concentration (creat-E) ranged from 28 to 862 micro mol/L (median 126). The linear correlation coefficient (R) of 1/cyst-C versus GFR (R = 0.937) did not differ from either that of 1/creat-J versus GFR (R = 0.918) or that of 1/creat-E versus GFR (R = 0.901). These coefficients had overlapping confidence intervals. The areas under the curve for cyst-C, creat-J and creat-E were 0.967, 0.977 and 0.924, respectively, and were not significantly different from each other. For cyst-C, the optimal cut-off was 1.1 mg/L. CONCLUSIONS: Serum cyst-C is equivalent to creat-J and creat-E as a marker for estimating the GFR in the paediatric population studied.

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BACKGROUND: Based on the data derived from the Modification of Diet in Renal Disease (MDRD) study, a new equation was developed for the estimation of glomerular filtration rate (GFR). This equation, which takes into account body weight, age, sex, serum creatinine, race, serum urea, and serum albumin, provided a more accurate estimation of GFR in patients with renal insufficiency. However, this prediction equation has not been validated in subjects with normal or supra-normal GFR. METHODS: In a cross-sectional study, we measured GFR by inulin clearance in 46 healthy controls and 46 non-complicated type 1 diabetic patients. In this study population, GFR was predicted by measured creatinine clearance, the Cockcroft-Gault formula, and the MDRD equation. RESULTS: In the healthy subjects, mean GFR (+/-SD) was 107+/-11 as compared to 122+/-18 ml/min per 1.73 m(2) in the diabetic patients. This difference in GFR was reflected by a lower serum creatinine (76+/-8 vs 71+/-8 micro mol/l) in the diabetic patients. In the healthy controls, median absolute differences (and the 50th-75th-90th percentile of percentage absolute differences) between predicted and measured GFR were 5.2 ml/min per 1.73 m(2) (4.9-9.8-18.5%) for creatinine clearance, 9.0 ml/min per 1.73 m(2) (8.6-14.3-24.6%) for the Cockcroft-Gault formula, and 10.7 ml/min per 1.73 m(2) (10.9-16.3-25.5%) for the MDRD equation. In the diabetic patients, these differences were 8.3 ml/min per 1.73 m(2) (7.6-9.3-13.0%) for creatinine clearance; 11.8 ml/min per 1.73 m(2) (10.1-16.0-22.5%) for the Cockcroft-Gault formula, and 18.8 ml/min per 1.73 m(2) (16.0-24.2-31.9%) for the MDRD equation. CONCLUSIONS: In subjects with a normal or increased GFR, the new MDRD-prediction equation of GFR is less accurate than creatinine clearance or the Cockcroft-Gault formula, and offers no advantage.

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