Relationships of serum levels of insulinlike growth factors with indices of bone metabolism and nutritional conditions in hemodialysis patients.

Insulinlike growth factor (IGF) I and IGF-II are synthesized in osteoblasts and stimulate proliferation, differentiation, and matrix synthesis in these cells. There is some evidence that IGFs act on bone cells not only by paracrine but also by endocrine pathways, suggesting that circulating IGFs may be of importance for the regulation of bone metabolism. On the other hand, the serum IGF-I level is also thought to be a good indicator of the nutritional conditions in hemodialysis patients. The present study was performed to analyze the correlations of circulating levels of IGF-I, IGF-II, IGF-binding protein (IGFBP) 1 and IGFBP-3 with biochemical markers of bone metabolism and parameters of the urea kinetic model which reflect nutritional conditions in hemodialysis patients. We also examined the differences between these relationships in male and female patients on hemodialysis. Sixty-two hemodialysis patients, 36 men (male group) and 26 women (female group), were included in this study. We measured the serum levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3. The bone mineral content (BMC) of the radius was measured by dual-energy X-ray absorptiometry. We calculated Kt/V, protein catabolic rate, and percent creatinine generation rate (%CGR). We also examined the relationships between serum levels of IGFs and BMC and the parameters of the urea kinetic model. It was found that the serum levels of IGF-I in the hemodialysis patients were almost the same as those in the control group. However, the serum levels of IGF-II, IGFBP-1, and IGFBP-3 in the hemodialysis patients were significantly higher than those in the control group. In the male group, the serum IGF-I levels showed a significant correlation with both serum intact parathyroid hormone levels and BMC, but no significant correlations between these indices were found in the female group. The serum levels of both IGF-I and IGF-II showed significant correlations with %CGR in the male group, but not in the female group. Stepwise multiple regression analysis was performed to clarify the relationship between serum levels of IGFs and BMC or %CGR. It was found that age, hemodialysis duration, serum intact parathyroid hormone levels, and sex were independent factors associated with BMC. The %CGR was associated independently with serum levels of IGF-I, and IGF-II and with the presence of diabetes mellitus. In conclusion, it is thought that serum levels of IGF-I and IGF-II can be used as indices of nutritional conditions in hemodialysis patients. However, the serum IGF-I level cannot be used as a marker of bone metabolism in hemodialysis patients.

Plasma adrenomedullin levels in patients on hemodialysis.

Adrenomedullin (AM) is a hypotensive peptide that has recently been isolated from human pheochromocytoma. In this study, we measured plasma AM concentrations in 54 patients on hemodialysis (HD) and examined the clinical significance. We also evaluated the effects of high-flux and low-flux dialysis membranes on plasma AM levels. The average value of plasma AM at pre-HD (4.44 +/- 0.16 fmol/ml) was significantly elevated compared with that in 44 healthy volunteers (1.31 +/- 1.41 fmol/ml) (p < 0.0001). The plasma AM concentrations at pre-HD showed a negative correlation with age and mean blood pressure (MBP) at pre-HD. The plasma AM concentrations at post-HD showed a negative correlation with MBP at post-HD and a negative correlation with the reduction rate of AM. Multiple regression analysis showed that age and MBP were independent factors associated with plasma AM at pre-HD and that MBP and reduction rate of AM were independent factors associated with plasma AM at post-HD. We investigated the differences between high-flux dialyzers (PS-UW, PS-N and FB-F) and a low-flux dialyzer (AM-BC-F), and we found that high-flux dialyzers removed plasma AM more efficiently than a low-flux dialyzer did. In addition, in 3 patients on HD, plasma AM levels decreased significantly during isovolumic dialysis using a high-flux dialyzer, despite the fact that there were no significant changes in MBP and ANP. In conclusion, elevation in plasma AM level causes a fall in MBP in patients on HD, therefore, removal of AM by HD treatment using a high-flux dialyzer contributes to the stability of blood pressure during HD.

Quantitative estimation of dietary energy deficiency and effects of its supplementation on protein nutritional status of nondiabetic uremic patients undergoing protein restricted dietary regimens.

In chronic renal failure (CRF) patients with a reduced protein intake, if the patients' energy intake could be estimated on the basis of biochemical data together with protein intake, it would be easier to provide them with adequate dietary treatment. Thus, from the relationship among the normalized protein catabolic rate (nPCR) and the intrinsic creatinine generation rate (%GCr) both calculated on the basis of 24-hr urine creatinine, as well as the daily dietary energy intake evaluated by a skilled nutritionist, we devised the following equation to estimate the amount of dietary energy deficiency (delta E) whose supplementation increases the %GCr of patients on protein-restricted dietary regimens to the target level (i.e., the dietary energy deficient amount). This was done by taking the %GCr of average nondiabetic hemodialysis patients of the same age and sex as a temporal target level: delta E = [31.22 - 1.97 (%GCr)0.6]/(nPCR)0.15. In order to examine the clinical usefulness of this equation, the daily dietary energy deficient amount calculated by the equation was supplemented with protein-free jelly. As a result, the %GCr increased from approximately three-fourths of the target level to the target level within 4 months.

Determination of bisphenol a in effluents of hemodialyzers.

This study was designed to determine whether bisphenol A (BPA) is eluted from hemodialyzers in which polycarbonate and polysulfone based on BPA are used as materials. Four types of polysulfone hemodialyzer (PS hemodialyzer: PS-A, PS-B, PS-C and PS-D) and an ethylene-vinyl alcohol copolymer dialyzer (EVAL hemodialyzer) were used in this study. In the PS-C, PS-D and EVAL hemodialyzers, polycarbonate was used in the case headers at both ends of the hemodialyzer. In in vitro experiments, the hemodialyzers were filled with reverse osmotic water, and BPA concentrations were measured. Saline solution (200 ml) was then circulated through a blood circuit tube connected to the hemodialyzer, and BPA concentrations in the saline solution were measured. In in vivo experiments, BPA concentrations in whole blood samples from hemodialysis patients treated with PS-C (n = 3) and PS-D (n = 3) hemodialyzers were measured. In in vitro experiments, BPA was detected in the effluents of the PS-C, PS-D and EVAL hemodialyzers. In in vivo experiments, BPA was detected in whole blood samples from hemodialysis patients treated with the PS-D hemodialyzer (mean value, 0.77 ppb). This is the first report of BPA elution from hemodialyzers in which polycarbonate and polysulfone are used, and also the first report of detection of BPA in whole blood samples from patients on hemodialysis.

Oxidative stress is reduced by the long-term use of vitamin E-coated dialysis filters.

BACKGROUND: Oxidative stress during hemodialysis is thought to promote the progression of vascular complications in hemodialysis patients. The protective role of vitamin E as a lipophilic antioxidant against oxidative stress has been widely investigated. Here we investigated the effects of a vitamin E-coated regenerated cellulose hollow fiber dialyzer (CL-EE) on oxidative stress compared with a polysulfone hollow fiber (CL-PS). METHODS: For at least three months before beginning the protocol, 10 nondiabetic (NDM) patients (70.0 +/- 7.5 years; 6 males and 4 females) and 8 diabetic (DM) patients (65.0 +/- 7.4 years; 4 males, 4 females) were dialyzed with CL-PS. After that, we treated all of the patients with CL-EE for six months. Malondialdehyde (MDA), advanced glycation end products (AGEs), and 8-hydroxydeoxyguanosine (8-OHdG) were monitored as biomarkers for oxidative stress at the start and then at one, three, and six months into treatment with CL-EE. RESULTS: Serum MDA, AGE, and 8-OHdG levels increased after the hemodialysis with CL-PS. The increase of the biomarkers was completely prevented by a single use of CL-EE. Long-term hemodialysis with CL-EE for six months significantly reduced the basal levels of the oxidant markers at one month for AGE and at six months for 8-OHdG in both DM and NDM patients. Serum MDA was reduced in only DM patients at three months. The improvement of the oxidative stress with CL-EE was more prominent in the DM patients. CONCLUSIONS: Long-term treatment with CL-EE efficiently improves the oxidative stress associated with hemodialysis and potentially reduces dialysis complications due to oxidative stress.

Familial interstitial nephritis with progressive renal failure.

We describe a 53-year-old woman with chronic interstitial nephritis and asymptomatic impairment of renal function. Seven members of her family were suffering from renal failure and underwent hemodialysis. At the time of their hospital admissions, they had shown evidence of end-stage renal failure at 40 to 50 years of age. Lack of proteinuria, hematuria, hypertension, hyperuricemia, hearing loss, and visual impairment were present before the deterioration of the renal function. Renal biopsy of the presented case indicated chronic interstitial nephritis without glomerular basement membrane abnormalities. Progressive decline of renal function and the inheritance pattern of autosomal dominance in this family suggested the diagnosis of familial interstitial nephritis.

The significance of serum homocysteine levels in diabetic patients on haemodialysis.

BACKGROUND: Atherosclerotic diseases are the major cause of mortality and morbidity in patients on haemodialysis (HD). Furthermore, the prognosis of diabetic patients on HD is especially poor due to atherosclerotic complications. Because homocysteine (Hcy), a sulfur-containing amino acid, is emerging as an important risk factor for atherosclerosis in patients with end-stage renal disease, we examined the significance of serum Hcy levels in diabetic patients on HD. METHODS: We measured total serum Hcy levels (tHcy) in 31 patients with diabetes mellitus on HD (DM group) and 37 non-diabetic patients on HD (N group), adjusting for age and HD duration. Linear regression analysis was used to assess the correlation of multiple variables to tHcy. RESULTS: The proportion of atherosclerotic disease in the DM group was significantly higher than in the N group. However, serum tHcy, serum creatinine and per cent creatinine generation rate in the DM group were significantly lower than in the N group. In the DM group, serum tHcy was positively correlated with creatinine, albumin and per cent creatinine generation rate, respectively. This was not the case in the N group. CONCLUSIONS: The demethylation pathway in methionine metabolism in the liver, which is linked directly to the creatinine generation system, may be disturbed in diabetic patients on HD. This may be the reason why serum tHcy and creatinine in diabetic patients on HD are lower than in non-diabetic patients on HD. Therefore, it is necessary to consider the possibility of an altered relation between serum tHcy and vessel disease when evaluating the atherogenic risk in diabetic patients on HD.

The significance of atherogenic indices in patients on hemodialysis.

Atherosclerotic diseases (ASD) are the major cause of mortality and morbidity in patients on hemodialysis (HD). To evaluate the significance and usefulness of atherogenic indices, we examined lipoprotein(a) (Lp(a)), remnant-like particles cholesterol (RLP.C), homocysteine (Hcy), cardiac troponin T (TnT), and ankle-arm blood pressure index (AABI) in 114 patients on HD (male 79, female 35; age 62.1 +/- 1.3 years). As a result, serum cardiac TnT and AABI levels in patients with diabetes mellitus (DM) (n = 33) were significantly higher than those in patients without DM (n = 81). In patients with cerebrovascular diseases (CVD), serum levels of both RLP.C and Hcy, and AABI levels were significantly higher than those in patients without CVD. In patients with coronary artery diseases (CAD), serum cardiac TnT and AABI levels were significantly higher than those in patients without CAD. In patients with peripheral vascular diseases (PVD), serum levels of both Hcy and cardiac TnT were significantly higher than those in patients without PVD. Multiple regression analysis did show that the presence of DM, serum Hcy levels and age were independent factors as- sociated with ASD: ASD = -0.348 + 0.426 x DM (scored: 0, absence; 1, presence) + 0.005 x Hcy (nmol/ml) + 0. 010 x Age (years) (p < 0.001). In conclusion, the presence of DM and advanced age are major determinants for atherosclerosis. In addition, serum Hcy levels are independent risk factors for atherosclerosis irrespective of the absence of DM.

Fatal pancreatitis associated with systemic amyloidosis in a rheumatoid arthritis patient.

We report here a case of severe acute pancreatitis associated with systemic AA amyloidosis in a 69-year-old rheumatoid arthritis (RA) patient. AA amyloid deposition was detected on the walls of small pancreatic arteries and arterioles. The acute pancreatitis was resistant to various interventions, and acute necrotizing pancreatitis and multiple organ failure developed. Although AA amyloidosis in RA patients is rarely complicated with acute pancreatitis, acute pancreatitis in such cases could be severe and intractable and might result in a fatal outcome.

Serum leptin concentrations in patients on hemodialysis.

Serum leptin concentrations in normal humans have been reported to correlate with the body mass index (BMI) as well as with the body fat mass. In this study, we measured serum leptin concentrations in 107 patients on hemodialysis, 30 of whom had diabetes mellitus as the cause, and examined the clinical significance. Furthermore, we evaluated the effects of high-flux dialysis membranes on serum leptin levels. Serum leptin concentrations had a linear correlation with BMI as well as with the percentage of body fat in patients on hemodialysis. The serum leptin concentrations showed a positive correlation with the serum concentrations of total cholesterol, low-density lipoprotein cholesterol, and triglyceride, the body weight, the BMI, and the percentage of body fat. The serum leptin levels were not different between the diabetic and the nondiabetic groups. The serum leptin levels in the nondiabetic group were nearly fourfold higher in women than in men. We investigated the differences in the rate of reduction in serum leptin after dialysis with polysulfone membrane dialyzers (PS-N and PS-UW) in comparison with a cellulose membrane dialyzer (AM-SD), and as a result, we found that the polysulfone membrane dialyzers removed serum leptin, while the cellulose membrane dialyzer did not. We conclude that in patients on hemodialysis, the serum leptin concentration is a valuable clinical marker of the body fat content and may also contribute to the evaluation of hyperlipidemia.

Fatal hyperammonemia in a patient with systemic lupus erythematosus.

We treated a 31-year-old woman with systemic lupus erythematosus, renal failure with nephrotic syndrome, and a long-standing seizure disorder, who developed severe hyperammonemia with a fatal outcome. Blood chemistry examination did not indicate liver disease, and amino acid concentrations did not suggest a defect in the urea cycle. Discontinuation of anticonvulsant treatment with valproic acid (VPA) failed to bring about improvement. We speculated that hyperammonemia in this case was induced by VPA, and the existence of other underlying factors, including the administration of aspirin and cimetidine, hypoalbuminemia, and renal failure might elevate the concentration of the serum free fraction of VPA.

[A case of scleroderma renal crisis with massive pericardial effusion and positivity on antiphospholipid antibody test].

A 47-year-old woman was admitted to our hospital for evaluation of general fatigue and dyspnea. She had been diagnosed with progressive systemic sclerosis (PSS) when she was 39 years of age, on the basis of Raynaud's phenomenon, proximal sclerosis, and pigmentation of the skin. On admission, her blood pressure was 206/128 mmHg. Funduscopy revealed grade III (Keith & Wagener) hypertensive retinopathy. Laboratory data showed positivity for anti-nuclear antibody and anticardiolipin beta 2 glycoprotein I antibody, and the plasma level of renin activity (PRA) was abnormally high. Chest X-ray and UCG revealed massive pericardial effusion. On the second hospital day, she was operated on for pericardiodiaphragmatic fenestration. The volume of pericardial effusion amounted to more than 2000 ml. Post operative malignant hypertension persisted. Laboratory data showed thrombocytopenia, hemolytic anemia, and acute renal failure. We diagnosed scleroderma renal crisis (SRC) associated with antiphospholipid syndrome. Following the initiation of angiotensin converting enzyme inhibitor (ACE-I) combined with calcium antagonist and alpha-one blocker, her blood pressure and PRA decreased. She also had been treated with aspirin 81 mg daily. These therapies were effective in recovering the platelet count and stopped the progression of anemia and renal failure. Although either the finding of large pericardial effusion or SRC is associated with poor prognosis in PSS, this case has had a good clinical course. In this case, the findings suggested that anti-phospholipid antibody may have contributed to the pericarditis and SRC.

Soluble P-selectin is released from activated platelets in vivo during hemodialysis.

During hemodialysis, platelets are activated across a dialyzer. Soluble P-selectin (sP-selectin) is a form of P-selectin which is a glycoprotein relocated from secretory granules to the surfaces of platelets and endothelial cells after these cells have been physiologically activated. To investigate whether sP-selectin is useful as a marker of platelet activation during hemodialysis, we measured the plasma concentration of sP-selectin by enzyme-linked immunosorbent assay in 6 patients hemodialyzed in our institute using regenerated cellulose (RC) membranes and thereafter polysulfone membranes. Concomitantly, we also measured the plasma concentration of platelet factor 4 and beta-thromboglobulin which are released from alpha-granules of activated platelets. During hemodialysis with RC membranes, the beta-thromboglobulin level was significantly increased 15 min (p < 0.05) and the sP-selectin level 15 (p < 0.05) and 180 min (p < 0.05) after initiation of dialysis on the venous side as compared with the arterial side of the hemodialyzer. During hemodialysis with polysulfone membranes, no significant variation in plasma beta-thromboglobulin and sP-selectin levels was detected. The platelet factor 4 level increased more significantly across a dialyzer 180 min after initiation of dialysis with RC than with polysulfone membranes (p < 0.01). The changes in plasma platelet factor 4 and beta-thromboglobulin levels demonstrated that platelets are more activated during hemodialysis with RC than with polysulfone membranes. The changes in plasma sP-selectin levels during hemodialysis with RC confirm that the release of P-selectin purely from activated platelets was detected by enzyme-linked immunosorbent assay. sP-selectin may be a marker of platelet activation during hemodialysis.

[Study on coagulation fibrinolytic systems in predialysis patients with chronic renal failure--comparison between patients with chronic glomerulonephritis and patients with diabetic nephropathy].

To clarify the abnormalities of coagulation and fibrinolytic systems on predialysis patients with chronic renal failure, we measured indices of coagulation and fibrinolytic systems in 33 predialysis patients whose creatinine (Cr) levels were over 3.0 mg/dl. We termed twenty-four patients with chronic glomerulonephritis the "CGN group". We also termed nine patients wit diabetes mellitus the "DM group". We measured thrombin.antithrombin III complex (TAT), alpha 2-plasmin inhibitor plasmin complex (PIC), D-dimer, protein C, protein S, thrombomodulin (TM), vitronectin, tissue plasminogen activator.plasminogen activator inhibitor-1 complex (tPAI-C) in theses two groups. Furthermore, we measured the same indices after 6 months in the CGN group. As a result, the plasma levels of both TAT, PIC, TM/Cr ration in the DM group were significantly higher that those in the CGN group, changes in both protein S activities and plasma levels of tPAI-C were reduced significantly after 6 months. In conclusion, the abnormalities of coagulation and fibrinolytic systems in predialysis diabetic patients were stronger than those in predialysis patients with CGN. Furthermore, these abnormalities were worsened after 6 months in predialysis patients with chronic renal failure.

Signal averaged electrocardiography (SAECG) in patients on hemodialysis.

Cardiovascular diseases are the major cause of mortality in patients on hemodialysis (HD). Recently, signal averaged electrocardiography (SAECG) has been developed to detect ventricular late potentials (LP) noninvasively from the body surface for identifying patients at sudden death or ventricular tachycardia. We performed SAECG in 42 patients before and after HD. As a result, postdialysis total filtered QRS duration (FQRS) was significantly increased compared with predialysis FQRS. Postdialysis duration of low amplitude signal under 40 microV in the latter part of QRS (LAS40) tended to increase compared with predialysis LAS40. Before HD, there were no patients with LP and only one patient (2.4%) with abnormal SAECGs. In contrast, after HD, there were three patients (7.1%) with LP and three more patients (7.1%) with abnormal SAECGs. Furthermore, there was a significant correlation between the changes in LAS40 (delta LAS40) and those in potassium (K) (delta K) during HD. We further examined the relation between LAS40 and the concentration of K, by comparing the correlation coefficient between patients in the high-K group (predialysis K > or = 5.0 mEq/L; 20 patients) and those in the low-K group (predialysis K < 5.0 mEq/L; 22 patients). In the low-K group, there was no significant correlation between delta LAS40 and delta K. However, in the high-K group, there was a significant correlation between delta LAS40 and delta K. In conclusion, SAECG indices worsened during HD, and an insufficient decrement of serum potassium by HD is suggested to have been an arrhythmogenic factor in the high-K group.

What is the best index of glycemic control in patients with diabetes mellitus on hemodialysis?

Since red blood cell survival time is shortened in patients with diabetes mellitus (DM) on hemodialysis (HD), it is unlikely that indices of glycemic control accurately reflect the glycemic state of these individuals. In this study, in order to determine the best index of glycemic control in diabetic patients on HD, we measured HbAlc, 1,5-anhydroglucitol (1,5-AG), fructosamine (Fr) and glycated albumin (GA) in 31 diabetic patients on HD (20 males and 11 females, mean age: 66.9 years), and examined the correlation between each index and predialysis plasma glucose level. Since the mean values of predialysis plasma glucose during the final 2 and 4 weeks before the study were best correlated with HbAlc, this parameter was considered to be the most reliable index of glycemic control in diabetic patients on HD. GA was more closely correlated with mean values of predialysis plasma glucose during the final 2 and 4 weeks, than any other index of glycemic control, followed by HbAlc. In conclusion, HbAlc is considered to be the most reliable index of glycemic control in diabetic patients on HD.

Plasma concentrations of natriuretic peptides in patients on hemodialysis.

The usefulness of plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and cyclic guanosine 3',5'- monophosphate (cGMP) as markers of fluid overload was examined in hemodialysis (HD) patients without diabetes mellitus. Plasma concentrations of ANP, BNP, CNP, and cGMP all decreased significantly during HD. Before HD, there was a strong correlation between plasma concentrations of ANP and those of BNP, and plasma concentrations of cGMP correlated significantly with those of all three natriuretic peptides. The cardiothoracic ratio also correlated significantly with plasma concentrations of ANP and those of BNP before HD. Systolic blood pressure correlated significantly only with plasma concentrations of CNP, both before and after HD. Changes in body weight during HD correlated only with those in plasma ANP; there was thus no correlation between changes in body weight and those in plasma CNP. In conclusion, only plasma ANP is a useful marker of the proper volume and dry weight of HD patients. Furthermore, CNP may participate in cardiovascular regulation in HD patients in a manner different from those of ANP and BNP.