Shigeru Nakai

Determination of Kt/V and Protein Catabolic Rate Using Pre- and Postdialysis Blood Urea Nitrogen Concentrations

We developed a new urea kinetic method for simultaneous determination of the Kt/V and protein catabolic rate (PCR) only from blood urea nitrogen (BUN) concentrations before and after a single dialysis session. Using this method, the parameters were calculated within 1.5 s even when a hand-held computer with a low central processing capacity is used. The total amount of urea eliminated during three dialysis sessions in 1 week is assumed to be equal to urea volume (Gw) generated over a 1-week period (Tw): [formula: see text]. Here, G is the generation rate, K is the dialyzer urea clearance, T is the dialysis time and C1, C2 and C3 are BUN during the respective dialysis session. If this equation and the equation expressing the urea kinetics during a single dialysis session are solved together, we have a solution for Kt/V and G. The thus-obtained Kt/V and G are corrected using the change in body weight. The corrected Kt/V showed a good correspondence with the parameter calculated with the classical method, and the midweek PCR derived from G determined by the present method being equivalent to the PCR averaged for a 1-week period determined by the classical methods.

In vitro modeling of paraxial and lateral mesoderm differentiation reveals early reversibility

Endothelial cells (ECs) are thought to be derived mainly from the vascular endothelial growth factor receptor 2 (VEGFR‐2)+ lateral mesoderm during early embryogenesis. In this study, we specified several pathways for EC differentiation using a murine embryonic stem (ES) cell differentiation culture system that is a model for cellular processes during early embryogenesis. Based on the results of in vitro fate analysis, we show that, in the main pathway, committed ECs are differentiated through the VEGFR‐2+ platelet‐derived growth factor receptor α (PDGFR‐α)− single‐positive (VSP) population that is derived from the VEGFR‐2+PDGFR‐α+ double‐positive (DP) population. This major differentiation course was also confirmed using DNA microarray analysis. In addition to this main pathway, however, ECs also can be generated from the VEGFR‐2−PDGFR‐α+ single‐positive (PSP) population, which represents the paraxial mesodermal lineage and is also derived from the DP population. Our results strongly suggest that, even after differentiation from the common progenitor DP population into the VSP and PSP populations, these two populations continue spontaneous switching of their surface phenotype, which results in switching of their eventual fates. The rate of this interlineage conversion between VSP and PSP is unexpectedly high. Because of this potential to undergo fate switch, we conclude that ECs can be generated via multiple pathways in in vitro ES cell differentiation.

Risk Factors for IgA Nephropathy: A Case-Control Study with Incident Cases in Japan

Background/Aim: Our previous study with prevalent cases suggested that some genetic, immunological and lifestyle-related factors increased the risk of immunoglobulin A nephropathy (IgAN). To confirm this hypothesis, we conducted another case-control study. Methods: The study included 116 incident cases and 276 sex-, age- and residence-matched controls in central Japan. Information on family and individual history and on lifestyle was collected using a self-administered questionnaire. The strength of association between IgAN and a potential risk factor was assessed by calculating an odds ratio. Results: A family history of chronic glomerulonephritis, susceptibility to the common cold, episodes of tonsillitis in the preceding year, preference for salty foods and a high intake of rice and n–6 polyunsaturated fatty acids (PUFA) were associated with an increased risk of IgAN. Coffee consumption and dietary calcium intake were somewhat negatively related to the risk. A significance of alcohol drinking, use of vitamin supplements, consumption of raw eggs and intake of nutrients other than n–6 PUFA and calcium, though previously suggested, was not shown in the present study. Conclusion: Our findings imply that some genetic factors, immune response to infections in the upper respiratory tract and nutritional imbalance would promote the development of IgAN.

Platelet GPIIb/IIIa Is Activated and Platelet-Leukocyte Coaggregates Formed in vivo during Hemodialysis

Background/Aim: During hemodialysis, platelets and leukocytes are activated and form platelet-leukocyte coaggregates in which GPIIb/IIIa (CD41/CD61) and CD62P (P-selectin) are involved. However, it is still controversial whether platelet activation and platelet-leukocyte coaggregate formation are dependent on the dialyzer membrane material. Method: We examined the appearance of activation-dependent antibody on platelets as an index of platelet activation, and the appearance of platelet-specific antigen on leukocytes as an index of platelet-leukocyte coaggregation, during hemodialysis in 7 patients treated using regenerated cellulose (RC) membrane and next using polysulfone (PS) membrane. In order to reduce the influence of factors other than dialyzer membrane material, this study was conducted in a prospective crossover fashion using a pyrogen-free bicarbonate dialysate. Moreover, flow cytometric techniques with whole blood were employed, which reduce artificial cell activation during the cell or plasma separation procedure. The platelet-specific monoclonal antibodies used in this study were anti-CD61, PAC-1 (which recognizes only the conformationally activated GPIIb/IIIa) and anti-CD62P. Results: Changes in the percentage of PAC-1-positive platelets were significantly greater during hemodialysis with RC than with PS. However, changes in the percentage of CD62P-positive platelets were not significantly different between hemodialysis with RC and PS. Changes in the percentage of CD61- or CD62P-positive leukocytes were significantly greater during hemodialysis with RC than with PS. Although changes in percentage of PAC-1-positive platelets did not parallel those of CD62P-positive platelets during hemodialysis, there was a significant positive correlation between the percentage of CD61-positive leukocytes and the percentage of CD62P-positive leukocytes. Conclusion: This study, conducted in a prospective crossover fashion using a pyrogen-free bicarbonate dialysate in order to reduce the influence of factors other than the dialyzer membrane material, demonstrated that both the degrees of GPIIb/IIIa activation and platelet-leukocyte coaggregation were greater during hemodialysis with RC than PS.

Estimation of dietary nutritional content using an online system with ability to assess the dieticians' accuracy

We developed an online system for estimating dietary nutritional content. It also had the function of assessing the accuracy of the participating dieticians and ranking their performance. People who wished to have their meal estimated (i.e. clients) submitted images of their meal taken by digital camera to the server via the Internet, and dieticians estimated the nutritional content (i.e. calorie and protein content). The system assessed the accuracy of the dieticians and if it was satisfactory, the results were sent to the client. Clients received details of the calorie and protein content of their meals within 24 h by email. A total of 93 dieticians (71 students and 22 licensed practitioners) used the system. A two-way analysis of variance showed that there was a significant variation (P=0.004) among dieticians in their ability to estimate both calorie and protein content. There was a significant difference in values of both calorie (P=0.02) and protein (P<0.001) estimation accuracy between student dieticians and licensed dieticians. The estimation accuracy of the licensed nutritionists was 85% (SD 10) for calorie content and 78% (SD 17) for protein content.

Changes in Mac-1 and CD14 Expression on Monocytes and Serum Soluble CD14 Level during Push/Pull Hemodiafiltration

Background/Aim: Employment of treated dialysate as replacement fluid raises concerns about exposure of patients to pyrogenic substances. This study was undertaken to evaluate the safety of treated dialysate as the replacement fluid for push/pull hemodiafiltration. Methods: In the present study, changes in the expressions of Mac-1 and CD14 on monocytes, which are upregulated by monocyte activation, were analyzed by flow cytometry, and the serum level of sCD14 which elevates by monocyte activation was measured by enzyme-linked immunosorbent assay (ELISA) during treatment in 7 patients on hemodialysis with regenerated cellulose (RC) membrane, polysulfone (PS) membranes and by push/pull hemodiafiltration (HDF) with PS membranes in a cross-over fashion. Results: During hemodialysis with RC, hemodialysis with PS or push/pull hemodiafiltration with PS, both Mac-1 and CD14 expressions on monocytes significantly increased by passing through the artificial kidneys, and, accordingly, the respective values downstream of the artificial kidneys were significantly higher than the predialysis values, even when the lipopolysaccharide level in dialysate was not detectable by Limulus assay. There was no significant variation in serum sCD14 levels during any of the hemodialysis with RC, hemodialysis with PS or push/pull hemodiafiltration. However, during hemodialysis with PS or push/pull hemodiafiltration with PS, changes in Mac-1 and CD14 expression on monocytes were significantly smaller than those during hemodialysis with RC. Conclusion: Monocytes are activated to a greater extent during hemodialysis with RC membranes than during push/pull HDF with PS membranes. We consider that push/pull HDF may be safer than hemodialysis with RC membrane and that it is as safe as hemodialysis with the PS membrane in terms of monocyte activation, when pyrogen-free dialysate is employed.

Effect of creatinine generation rate on the relationship between hemodialysis prescription and health-related quality of life

Abstract Reports to date have indicated no strong relationship between hemodialysis (HD) prescription and health-related quality of life (HRQOL). However, none of these reports addressed the effect of protein-energy nutritional status on the relationship between HD prescription and HRQOL. Thus, taking the creatinine (Cr) generation rate as a marker of protein-energy nutritional status, we divided maintenance HD patients into two groups with high and low Cr generation rates compared with the average rate. We then investigated the relationship between HD prescription and HRQOL in the two groups. The subjects were 1887 patients receiving HD three times weekly. Together with conducting an HRQOL survey using SF-36 on these patients, we surveyed Kt/V, K/V, and Cr generation rate. In the present study, K/V (the marker of HD efficiency) was obtained by dividing Kt/V by the duration of the HD session. Lower HRQOL scores tended to be associated with higher Kt/V only in patients with a low Cr generation rate; in patients with a high Cr generation rate, almost no association was found between Kt/V and HRQOL scores. In patients with a low Cr generation rate, lower HRQOL scores were associated with higher K/V, whereas in those with a high Cr generation rate, there was almost no association between K/V and HRQOL scores. In terms of duration of the HD session, almost no relationship was found between HD prescription and HRQOL scores in other patient group. These results suggest that a high HD efficiency lowers HRQOL among patients with poor protein-energy nutritional status. In such patients, HRQOL could be improved by extending the duration of the HD session with lowering of the HD efficiency.

Predialysis serum albumin concentration and creatinine generation rate do not reflect the same pathophysiologic status

BackgroundWhereas the creatinine generation rate may reflect only the protein nutritional status by way of muscle mass, the predialysis serum albumin concentration may well reflect a variety of aspects of a patients pathophysiologic status, including the protein nutritional status. The aim of this study was to clarify whether or not serum albumin concentration and the creatinine generation rate reflect the same pathophysiologic status.MethodsThe risk of death associated with the creatinine generation rate was studied with and without adjustment for the serum albumin concentration in 1588 patients undergoing hemodialysis. A comparison was also made between the death risk associated with serum albumin concentrations with and without adjustment for the creatinine generation rate. Possible correlations between the creatinine generation rate and serum albumin concentration were evaluated.ResultsThe death risk associated with the creatinine generation rate was little changed when adjusted for serum albumin concentration. However, the death risk associated with serum albumin concentration remained high even after being adjusted by the creatinine generation rate. Moreover, the correlation was very weak between the creatinine generation rate and the serum albumin concentration.ConclusionsSerum albumin concentration and the creatinine generation rate do not reflect the same pathophysiologic status.

Involvement of oxidative stress in the accelerated formation of pentosidine in patients with end‐stage renal failure

SUMMARY: Advanced glycation end products (AGEs) have been found to accumulate in the amyloid deposits, skin and plasma of haemodialysis patients (HD), implicating the possible involvement of AGE‐modified protein in pathogenesis in dialysis‐related amyloidosis. Pentosidine, an AGE cross‐link, is a specific marker for AGEs. Plasma pentosidine levels in HD patients were increased dramatically. In the present study, plasma pentosidine, fructoselysine, advanced oxidation protein products (AOPP) and glutathione peroxidase (GSHPx) levels were measured to elucidate the role of oxidative stress in pentosidine formation in nondiabetic HD patients. Plasma pentosidine did not correlate with fructoselysine; plasma AOPP levels were significantly higher than those in normal subjects (201.45 ± 57.93 vs. 55.91 ± 6.57 μmol/L, P<0.001) and correlated positively with plasma pentosidine in HD patients (r=0.52, P<0.005); plasma GSHPx levels were significantly lower than those in normal subjects (168.40 ± 65.08 vs. 348.87 ± 86.10 U/I, P<0.001) and correlated negatively with plasma pentosidine (r=0.54, P<0.001) in HD patients. Decreased GSHPx levels may lead to the accumulation of hydrogen peroxide. These findings implicate the involvement of oxidative stress in the accelerated formation of pentosidine in uraemia and suggest that pentosidine could be considered as an oxidative stress biomarker to estimate the degree of oxidative‐stress‐mediated protein damage.

Comparison of nephrotoxicity of pirarubicin and doxorubicin

BackgroundOur objectives were to determine whether pirarubicin induces nephrotic syndrome or chronic renal failure similar to doxorubicin in rats; and to compare the nephrotoxicity of pirubicin with that of doxorubicin.MethodsWistar rats were given doxorubicin (6.5 mg/kg and 3.25 mg/kg) or pirarubicin (9 mg/kg). The lethal dose 50 for doxirubicin is 13 mg/kg, and for pirarubicin, 18 mg/kg. In the pirarubicin groups, additional doses of 9 mg/kg or 4.5 mg/kg of pirarubicin were given 36 days after the first injection. We measured urinary protein, BUN, serum creatinine, and total cholesterol, and performed histologic studies of the kidneys.ResultsRats given doxorubicin (6.5 mg/kg or 3.25 mg/kg) showed severe persistent proteinuria. Hypoalbuminemia and hypercholesterolemia appeared after the doxorubicin injection. BUN and creatinine in the doxorubicin (6.5 mg/kg) group of rats began to increase significantly after 10 weeks, and the rats died within 11 weeks. Pirarubicin groups did not show any significant increase in urine protein after 36 days. After an additional injection of 9 mg/kg of pirarubicin, the rats showed an increase in urine protein. However, the pirarubicin-treated rats did not show nephrotic syndrome or chronic renal failure during the observation period.ConclusionBecause pirarubicin has far less nephrotoxicity than doxorubicin, it would be a safer and useful antitumor drug.