Initiation of dialysis depends upon several parameters including medical and non-medical reasons. Among the medical parameters measured or calculated creatinine clearance from plasma creatinine concentration seems to be the most reliable factor although clinical parameters such as gastro-intestinal disorders, cardiovascular, hematological, neurological manifestations and last but not least general status of the patient tend to play a determinant role in the decision of initiating dialysis. Dialysis is usually initiated for patients with a normalized creatinine clearance of 5 ml/min?E1 .73 m² but optional dialysis could be initiated from a normalized creatinine dearance of 10 ml/min?11.73 m², in case the capability of the patient and the physician to tolerate the burden of uremic syndrome is overcome. Rather than employing dialysis too late, it now seems advisable to initiate dialysis earlier in the course of chronic renal failure. Actually, retrospective analysis of 167 over 625 cases records from 1981 to 1985 and of 178 over 700 case records from 1986 to 1990 in the Department of Nephrology, Necker Hospital, plasma creatinine concentration at initiation of dialysis of the two period was 1044±17 and 981±13 mol/L respectively, corresponding to a creatinine clearance of 6 and 7 ml/min. It is clear now that management of chronic renal failure patients should be considered as a whole and initiation of dialysis is the end point of this global strategy. Definitely, optimal time for initiating dialysis should take into account various parameters, both biological and clinical as well as associated parameters such as age of the patient and involved systemic disease.

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Production of extracellular matrix (ECM) by mesangial cells (MCs) contributes to progressive glomerulosclerosis. Our previous immunocytochemical studies on ECM production by MCs [1] were extended by examining the gene expression and protein synthesis using Northern blotting and ELISA. ELISA demonstrated that fetal calf serum (FCS) stimulated the synthesis of collagen I (CI), III (CIII) and IV (CIV), and laminin (LM). At and after confluence, the amounts of CIII, CIV and LM per DNA amount began to decrease, whereas that of CI did not. Northern blotting indicated that the mRNA expressions for CIV and LM were transiently increased by FCS. The mRNA expressions for CI and CIII decreased until confluence and then returned to the initial levels. These results suggest that FCS and cellular confluence affected the synthesis of ECM at both the level of gene expression and protein synthesis. The mRNA expressions for CIV and LM paralleled the protein synthesis and appeared tightly regulated. CI and CIII synthesis and mRNA expression were not coordinate and were not regulated in the same manner as the basement membrane matrix components.

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The effects of various cytokines including interleukin-1β, -2, and -6, tumor necrosis factor- α, and granulocyte-macrophage colony stimulating factor on the DNA synthesis of cultured rabbit renal cortical tubular cells were investigated. Among these cytokines, it was found that only interleukin-1β could stimulate the DNA synthesis of cultured renal tubular cells, while interleukin-6 mildly suppressed the DNA synthesis of such cells. Interleukin-1β and -6 are produced by mesangial cells. The above results suggest that these cytokines may regulate the growth of tubular cells via the urinary flow in the nephron.

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In order to investigate the effect of saline loading on the atrial natriuretic peptide (ANP) in the central nervous system (CNS), time course measurements of the ANP content in the cerebrospinal fluid (CSF), blood pressure, water and electrolyte balances were carried out after saline loading in rats. Cisternal saline loading (120 ml/day) was found to induce a significant increase in urinary volume and electrolyte excretion, and to cause an initial rise in mean arterial blood pressure (MAP) in WKY rats. The ANP content in the CSF was significantly increased after saline loading, as compared to that in the control period. The ANP in both the plasma and CSF revealed a significant increase over the control values following chronic saline loading. Based on these results, it is suggested that the ANP in the CSF could exert a regulatory effect on the blood pressure and water balance, either by a direct action on the kidney or indirectly via an action on the CNS.

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Histopathological analysis was performed in the first renal biopsy specimens of patients over and under 10 yrs of IgA nephritis. They were divided clinically into two groups, the one with remission and the other with prolonged disease state respectively. Increased mesangial sclerosis, frequent occurrence of segmental glomerular lesions and tubulointerstitial change were significantly evident in the group with prolonged disease state. It is suggested that similar glomerular events are progressing in IgA nephritis which is carried over to adult age.

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Rat kidney tissue was quickly frozen, fractured and deeply etched. A replica was prepared by shadowing with platinum and carbon. The proximal tubular basement membrane was found to be different from that in conventional ultrathin sections. The lamina lucida was not electron translucent but filled with a traversing filamentous structure, which connected the tubular cell membranes with the lamina densa. The lamina densa had a three-dimensional polygonal meshwork structure. This meshwork was composed of fibrils (6-9 nm in thickness). In the lamina reticularis, collagen fibrils and microthreads formed a loose network structure. The traversing filamentous structure in the lamina lucida might serve as an anchorage for the cell membranes and extracellular matrices.

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The glomerular injuries in 129 cases of IgA nephropathy (IgA-N) were examined ultrastructurally with special reference to the glomerular basement membrane (GBM) deposits and capillary loop abnormalities, and the correlation between these findings and the clinicopathological data was analyzed. The following results were obtained. 1) The degree of daily excretion of urine protein (UP) and creatinine clearance (Ccr) revealed a significant correlation with the degree of mesangial hypercellularities and the frequency of segmental lesions. 2) All sites of GBM deposits, and discontinuity and/or splitting among the GBM abnormalities showed a significant relation to the severity of proliferation and segmental lesions. 3) The GBM deposits, discontinuity and splitting showed a significant relation to the degree of UP and Ccr. We speculate therefore that capillary loop deposits and/or capillary loop discontinuity and splitting could represent histological prognostic factors for an unfavorable outcome in IgA nephropathy.

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To study the relations between renal tubular disorder and glomerular dysfunction in the early phase of insulin-dependent diabetes mellitus (IDDM), we performed concomitant measurements of urinary β-D-N-acetyl glucosaminidase (NAG), β2-microglobulin (BMG), and microalbumin in 29 of pediatric patients with IDDM, 15 normal controls, and 83 patients with non-diabetic ketoacidosis. Urinary NAG levels were significantly elevated in the IDDM patients compared with controls. Urinary BMG levels were also elevated in IDDM, however, they were not as prominent as NAG levels. Although urinary microalbumin levels were elevated in the IDDM patients, statistical analysis did not show any significant difference between the IDDM patients and controls. Urinary NAG and BMG concentrations were also increased in patients with non-diabetic ketoacidosis, suggesting a toxic effect of ketone bodies to renal tubular cells. Statistically significant correlations were noted both between urinary NAG and microalbumin and between urinary BMG and microalbumin. These results suggest that, in early phase of IDDM, microalbuminuria is preceded by elevations in urinary NAG and BMG levels, and that keton bodies have deleterious effects on renal tubular cells.

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We investigated the early changes of tubules and effect of the oral adsorbent, AST-120, on the early changes of tubules in rats with chronic renal failure. Sprague-Dawley rats were divided into two groups with and without AST-120, after 3/4 nephrectomy. Although there were no significant differences in levels of blood urea nitrogen, serum creatinine, creatinine clearance, inulin clearance, para-aminohippuric acid clearance and urinary N-acetyl-β-D-glucosaminidase at week 8 between the two groups, the amount of 24-hour urinary protein excretion and the direct systolic blood pressure at week 8 were significantly decreased in the group with AST-120. Examinations by light microscopy at week 8 revealed that proteinaceous casts in the tubules, tubular dilatation and infiltration of monocytes into the interstitium in the group with AST-120 were less prominent than those in the group without AST-120. A significant difference in numbers of proteinaceous casts was noted at week 8 between the two groups. In rats with chronic renal failure at the early stage, it is concluded that the formation of proteinaceous casts, resulting in tubular damage, is increased and that AST-120 delays the occurrence of proteinaceous casts by delaying the increase in urinary protein excretion.

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Urea kinetic modeling (UKM) is often regarded as the best method for assessing the dialysis adequacy and consequently for the prescription of treatment time. However, other parameters are involved in the monitoring of end stage renal disease (ESRD) patients. Kt/V-urea and protein catabolic rate (pcr) were evaluated in 53 ESRD patients (25males and 28 females; mean age, 60±2 years old; mean duration, 80±11 months), twice at an interval of 4 months, and pre-dialysis concentration of (pre-DC) plasma potassium, bicarbonate, calcium and phosphate were measured. The pre-dialysis systolic blood pressure and hematocrit were also recorded. The numbers of patients who were within the optimal range of Kt/V-urea and pcr recommended by Gotch and Sargent were 36 (67.9%) and 39 (73.6%), respectively, at the first control period, and 39 (73.6%) and 44 (83.0%) at the second control period. However, only about 50% of the patients were within the optimal range of pre-DC plasma calcium, phosphate and bicarbonate. Furthermore, very few patients fulfilled the conditions for all the parameters. It is concluded that (1) UKM is required to describe the domain of dialysis prescription, and (2) other parameters which are not dependent so much on dialysis should be taken into account for assessing the adequacy of dialysis.

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Since it has been reported that correction of anemia in long-term hemodialysis patients by using human recombinant erythropoietin (r-HuEPO) is associated with improve sexual function, we conducted the present study to evaluate the changes in sex hormones as well as sexual function after r-HuEPO administration (1500 to 4500 IU per dialysis) for a year in patients on regular hemodialysis. Thirteen patients receiving regular hemodialysis entered this study. Their median age was 43 years. Along with correction of anemia (the hematocrit increased from 20 to 28%), testosterone (T) increased from 2.4±0.1 to 2.6±0.2ng/ml, follicular stimulating hormone (FSH) increased (29±5 to 73±7 mIU/ml), luteinizing hormone increased (69±14 to 160±21IU/ml) and prolactin decreased (all changes are significant at p<0.05). However, the improvement of sexual function was not remarkable. Only 2510 of the uremic patients treated with r-HuEPO showed amelioration of this function. From the present data, it does not seem likely that therapy with r-HuEPO induces directly amelioration of sexual function through changes in sex hormones.

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The diagnostic significance of urinary sialic acid (SA) determinations was evaluated in relation to the histological findings of renal biopsy specimens . The subjects enrolled in this study comprised 82 diabetics. They were divided into 4 groups according to Gellman's criteria, namely D₀, D_I, D_II and D_III-IV Thirty non-diabetic healthy volunteers were used as controls . The urinary SA was measured by high performance liquid chromatography, and the urinary albumin excretion was estimated by solid phase radioimmunoassay . In addition, urine samples were assayed for N-acetyl-β-D-glucosaminidase (NAG) and β₂-microglobulin (S 2MG). The urinary level of total SA (under conditions of hydrolysis) was significantly increased in the D_II and D_III-IV groups as compared to the controls; however, a similar value was observed in the D₀, D_I and control groups. The urinary level of glycoprotein-bound SA was significantly increased in all diabetics as compared to the control group, and was significantly higher in the DD_II and D_III-IV groups than in the D₀ and D_I groups. The bound-SA/total-SA ratio (B/T ratio) showed a significant increase with respect to the progress of diffuse lesions. A weak correlation was noted between the B/T ratio and urinary protein excretion. However, there was no correlation between the B/T ratio and other indices. The urinary SA is considered to represent a useful indicator for estimating diabetic nephropathy.

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Twenty-one male children and 3 male adults with essential hypertension were infused with physiological saline solution (15ml/kg/hr) for 1 hr after they had been supine for 90 min . The blood pressure and heart rate were monitored, and blood was taken twice before and after the infusion to measure the plasma Na-K ATPase inhibitor. After saline infusion, both the plasma Na-K ATPase inhibitor and blood pressure increased significantly in the hypertensive adults, and the number of Na pump sites decreased. However, such changes were not observed in the hypertensive children . These findings suggest that circulating Na-K ATPase inhibitor may not appear following acute saline infusion in hypertensive children unlike in hypertensive adults, and that the mechanisms regulating cell membrane sodium transport and high blood pressure may differ between hypertensive children and adults.

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A 55-year-old man was referred to us for evaluation of hypertension and hypokalemia. He had been administered glycyrrhizin from one year before admission for the treatment of chronic hepatitis. On admission, his blood pressure was 230/105 mmHg; serum potassium, 2.4mEq/l; the plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were undetectable. His blood pressure, potassium, PRA and PAC returned to normal within about 4 weeks after discontinuation of the glycyrrhizin. Re-administration of glycyrrhizin caused increases in PRA and PAC. His urinary cortisol excretion was increased and urinary cortisone excretion decreased, while his serum cortisol level remained unchanged. Supplementation of dexamethasone led to a decrease in blood pressure, and increased levels of serum potassium, PRA, and PAC. These results suggest that increased renal cortisol as a result of decreased conversion to cortisone might play an important role in the development of pseudoaldosteronism as well as in its own mineralocorticoid activity.

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The present study was undertaken to examine the effects of excess factor D build-up in the body of end-stage renal disease (ESRD) patients upon the activation of the alternative pathway and the terminal pathway in the fluid phase. First, to clarify the effect of excess factor D on the alternative pathway, purified factor D from an ESRD patient was added to normal serum and the changes in concentrations of C3a-des-Arg and C5a-des-Arg were investigated. The results showed that once the serum factor D level reached a concentration corresponding to 15μg/ml in the serum of the ESRD patient, the C3a-des-Arg and C5a-des-Arg levels had climbed to about 1.7-fold the concentration in normal serum. Next, in order to clarify the effect of excess factor D on the terminal pathway, purified factor D was added to normal serum, and the changes in C5b6 generation were examined. The results indicated that as the factor D level increased in the serum, the C5b6 level rose gradually also; and when the factor D concentration reached 15μg/ml, the C5b6 generation had risen to approximately 1.5-fold the level in normal serum. The present results therefore suggest that factor D build-up in ESRD patients provides a uremic toxin that can cause abnormal activation of the whole complement cascade.

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