Yukio Yuzawa

Background. Renal fibrosis, characterized by the accumulation of extracellular matrix (ECM), is a common histopathological feature of progressive renal disease of diverse etiology. Interaction between transforming growth factor-β (TGF-β) and TGF-β type II receptor (TGF-βIIR) may play an important role in the ongoing fibrotic process. TGF-βIIR and TGF-β have been reported to be up-regulated in human glomerulopathies. In order to block the TGF-β system, many studies have inhibited TGF-β itself, but not its receptors. Our study explored the effects of fully human monoclonal antibody against TGF-βIIR (hTGF-βIIRAb) on experimental proliferative glomerulonephritis. Methods. hTGF-βIIRAb was generated from Xenomice. The expression of TGF-βIIR was studied by immunohistochemistry in normal and anti-Thy-1 nephritis rats. hTGF-βIIRAb or control Ab was injected intraperitoneally at day 0 and day 4 of anti-Thy-1 nephritis, and rats were sacrificed at day 7. Effects of hTGF-βIIRAb were assessed by histological and immunopathological measurements. Results. The specificity of hTGF-βIIRAb was confirmed by ELISA and Western blot analysis. By immunostaining, TGFβIIR expression was up-regulated in the proliferative lesions of anti-Thy-1 nephritis at day 7. In the hTGF-βIIRAb-treated group, the extent of mesangial expansion was less than that in the control group. By immunohistology, α-smooth muscle actin, fibronectin-EDA, and type I collagen were significantly reduced in the hTGF-βIIRAb-treated group. Conclusions. Anti-TGF-βIIR antibody ameliorated ECM accumulation in anti-Thy-1 nephritis. Our data suggest that TGF-βIIR may be one of the therapeutic targets, and that fully human monoclonal antibody against TGF-βIIR may have a new therapeutic potential for renal fibrosis.

Background. As previously reported, the membrane-bound complement regulator at the C3 level (Crry/p65) is important in maintaining normal integrity of the kidney in rats. However, the role of a complement regulator at the C8/9 level (CD59) is not clear, especially when activation of complement occurs at the C3 level. The aim of this work was to elucidate the in vivo role of CD59 under C3 activating conditions. Methods. Two monoclonal antibodies, 5I2 and 6D1, were used to suppress the function of Crry and CD59, respectively. In order to activate alternative the pathway of complement, the left kidney was perfused with 5I2 and/or 6D1 and was recirculated. Results. In the kidneys perfused with 5I2 alone, deposition of C3 and membrane attack complex (MAC) was observed in the peritubular capillaries, vasa recta, and tubular basement membranes. Cast formation, tubular dilation and degeneration, and cellular infiltration were observed at days 1 and 4, and they recovered by day 7. Further suppression of CD59 by 6D1 significantly enhanced the deposition of MAC and worsened the already exacerbated tubulointerstitial injury. These effects of 6D1 were dose dependent. Perfusion with 6D1 alone did not induce histologic damage or MAC deposition in the tubulointerstitium. Conclusions. In rats, CD59 maintains normal integrity of the kidney in collaboration with Crry in rats against complement-mediated damage in vivo.

A 27-year-old man suffering from severe swelling and pain in his right arm was referred to our hospital. He showed signs of acute renal failure (ARF) with severe dermatitis of his right arm. Three days before being admitted, he accidentally touched some kind of marine organism with his right hand while snorkeling in the Sulu Sea around Cebu Island. Within a few minutes, he was experiencing severe pain in his right hand. Then his right hand gradually became swollen. The marine creature responsible for this injury was thought to have been a sea anemone, which is a type of coelenterate. Histologic findings of a renal biopsy indicated that acute tubular necrosis (ATN) had caused ARF in this patient's case. Supportive therapies improved renal function of this patient, and steroid pulse therapy attenuated the severe skin discoloration. The ATN was thought to have been caused by the poison from a sea anemone because there were no other conceivable reasons for the patient's condition. This is the first time that a marine envenomation case has been reported in which the sting of a sea anemone has caused ATN without the failure of any other organs. (C) 2000 by the National Kidney Foundation, Inc.

The presence of plasma proteins in the tubular lumen has variety of adverse effects on the tubular cells. Among various plasma proteins filtered through glomerular barrier, complement has been proven as the possible candidate inducing tubulointerstitial injury. To study the role of intratubular complement activation in proteinuric patients, complement activation products (CAP) at C3 level (iC3b and Bb) and C9 level (membrane attack complex) were measured in both plasma and urine of patients with minimal change nephrotic syndrome (MCNS), focal glomerular sclerosis, IgA nephropathy, membranous nephropathy, and diabetic nephropathy. For evaluation of the effect of metabolic acidosis on the intratubular complement activation, urinary CAP were measured before and after sodium bicarbonate administration in patients with renal insufficiency. The following results were obtained: (1) Patients with focal glomerular sclerosis and diabetic nephropathy showed the highest level of urinary CAP excretion rate (unit/creatinine), while MCNS revealed no increase. (2) Patients with membranous nephropathy showed a unique finding, i.e., isolated increase of membrane attack complex excretion. (3) There was no significant correlation between urine and plasma levels of CAP. (4) Except for MCNS patients, the urinary excretion rate of CAP significantly increased when the level of proteinuria exceeded the nephrotic range, and it was significantly correlated with the serum creatinine level. (5) Urinary CAP excretion rate significantly decreased 2 wk after sodium bicarbonate administration without affecting the level of proteinuria or plasma CAP. These results suggest that the degree of intratubular complement activation correlates with the level of proteinuria, type of glomerular disease, impairment of renal function, and metabolic acidosis.

Persistent proteinuria and tubulointerstitial lesions are important signs of progressive renal disease. The purpose of this study was to assess the role of complement in the development of tubulointerstitial lesions in rats with proteinuria due to primary glomerulonephritis. Mesangial proliferative glomerulonephritis was induced in mononephrectomized rats by intravenous injection of monoclonal antibody (mAb) 1-22-3 (Clin Exp Immunol 102: 181-185, 1995). As early as 24 h after the injection, proteinuria became evident, persisted throughout the observation period, and was associated with mesangial cell proliferation and tubulointerstitial lesions when examined at 7 and 14 d after mAb administration. Deposition of rat C3 and C5b-9 was observed at the luminal surface of proximal tubules and in cellular debris present in the tubular lumen (group I). Rats injected with mAb 1-22-3 and depleted of complement by injections of cobra venom factor starting at day 3 developed glomerulonephritis and proteinuria comparable to rats of group I, but complement deposition in the tubules and the tubulointerstitial lesions were markedly reduced (group II). Rats in group IU were injected with mAb and, from day 3, with soluble complement receptor type 1, which became detectable at the luminal surface of proximal tubules and in the urine. Deposition of C5b-9 in tubular cells was not detectable, and the severity of tubulointerstitial lesions was reduced compared with rats in group I. These results indicate that, in this model of primary mesangial proliferative glomerulonephritis with proteinuria, the development of tubulointerstitial lesions is associated with activation of serum complement at the level of tubular brush border, and tubulointerstitial lesions can be reduced by inhibition of complement activity.

The role of the inducible L-selectin ligand was studied in complement-dependent acute dermatitis in rats. Although mAbs against typical sialyl Lewis(x) (CSLEX-1 and SNH-3) did not react with skin venules, a sialyl Lewis(x)-like epitope defined by mAb 2H5 (2H5-Ag) was de novo expressed on the endothelial cells of skin venules in the area of inflammation. Expression of 2H5-Ag increased concomitantly with the progression of inflammation. 2H5-Ag was identified at the 75-, 150-, and 180-kDa bands when inflammatory skin tissue was analyzed by Western blotting. In contrast, P- and E-selectins were not detectable. The role of 2H5-Ag in this model was studied in in vitro and in vivo methods. First, 2H5 was iv injected 15 min before induction of dermatitis. 2H5 bound to skin venules and significantly reduced the neutrophil infiltration and plasma protein leakage. In contrast, CSLEX-1, mAb ARP2-4 (P-selectin blocker), or mAb ARE-5 (E-selectin blocker) had no effects. Second, adhesion of isolated rat neutrophils to the inflammatory skin section was inhibited significantly when the sections, but not neutrophils, were preincubated with 2H5. Third, fluorescein-labeled normal rat neutrophils were injected into a rat 10 h after induction of dermatitis. The number of labeled neutrophils infiltrated into the inflammatory site was reduced significantly when they were preincubated with HRL-3 (blocking mAb against rat L-selectin), but not with 2H5 or HRL-4 (nonblocking mAb against rat L-selectin). These data show that de novo expressed 2H5-Ag/L-selectin adhesion pathway contributes to the development of acute complement-dependent inflammation in the skin.

In the kidneys of anti-glomerular basement membrane (anti-GBM) antibody disease, binding of antibodies to tubular basement membrane (TBM) is often observed. The present work was performed to explore the mechanisms of binding of anti-GBM antibodies to TBM in vivo with special reference to 5I2Ag, a rat membrane inhibitor of complement which regulates complement activation at C3 convertase level. To suppress functions of renal 5I2Ag, F(ab')2 fragment of 5I2 (a neutralizing mAb against 5I2Ag) was perfused in the left kidney and then blood circulation was restored. Mild proteinuria (< 10 mg/16 hr) was observed during first several days. Five days later, there were tubulointerstitial injuries defined by tubular vimentin staining and leukocyte infiltration. Significant deposition of C3 was observed in the capillaries and in TBM. In rats intravenously injected with rabbit anti-rat GBM antibodies five minutes after kidney perfusion with 5I2, strong binding of rabbit IgG to TBM was observed at one and five days after injection. Although these rats showed mild proteinuria comparable to those perfused with 5I2 and those injected with normal rabbit serum, tubulointerstitial injury was significantly enhanced at Day 5. In contrast, rats perfused with irrelevant mAb and injected with anti-GBM antibodies did not show any significant binding of antibodies to TBM nor tubulointerstitial injury. Furthermore, rats which were made proteinuric by puromycin aminonucleoside and injected with anti-GBM antibodies did not show any significant binding of rabbit IgG to TBM. These results indicate that 5I2Ag, a rat membrane inhibitor of complement at the C3 convertase level, regulates vascular permeability in the living kidney, and that dysfunction or decreased expression of this molecule leads to increased accessibility of anti-GBM antibodies to TBM.

The kidney widely expresses membrane-associated complement regulatory proteins (membrane inhibitors of complement). The aim of this work was to evaluate the roles of these molecules in rat kidneys in vivo. To suppress functions of rat membrane inhibitors of complement, two mAbs, 512 and 6D1, were used. 512 and 6D1 inhibit functions of membrane inhibitors of complement at C3 level (rat Crry/p65) and C8/9 level (rat CD59), respectively. F(ab')2 fragment of 512 or 6D1 was perfused in the left kidneys, and perfusate was discarded from the renal vein. After perfusion, the left kidneys were connected to systemic circulation. In rats perfused with 512, mouse IgG was found in glomeruli, peritubular capillaries, vascular bundles, and tubules 15 min after recirculation. Binding of C3 and C5b-9 was evident in these areas. 1 d after perfusion with 512, cast formation, dilatation of tubular lumen, and tubular cell degeneration were observed. At day 4 through day 7, significant mononuclear cell infiltration and proximal tubule damage were observed. These changes were completely prevented by complement depletion. Rats perfused with 6D1 showed the binding of mouse IgG in the similar areas as 512, but C3 or C5b-9 deposition was nut observed. Rats perfused with 6D1 or vehicle only did not show any pathology in the left kidneys. These results suggest that rat Crry/p65 plays protective roles against spontaneously occurring indiscriminate attack to tubulointerstitial tissues by autologous complement and that rat Crry/p65 is one of the important factors to maintain normal integrity of the kidney in rats.

The kidney is an organ where complement-mediated tissue injuries take place by various stimuli. To assess how the kidney is protected from the autologous complement attack, comparative localization of decay accelerating factor (DAF), membrane cofactor protein (MCP) and 20 kDa homologous restriction factor (HRF20) was studied in the normal human kidney. Specific monoclonal antibodies to DAF, MCP and HRF20 were used for the study. Studies by immunofluorescence and immunoelectron microscopy showed that the distribution of each protein in the kidney was complementary to each other in most parts. MCP and HRF20 were clearly seen in the glomerular capillaries, while DAF was only faintly observed. Juxtaglomerular apparatus was abundant in DAF and MCP but not in HRF20. HRF20 was most strongly expressed in the peritubular capillaries where MCP was not detectable. Basolateral membranes of the proximal tubules and collecting ducts expressed MCP strongly, while there was no expression of DAF in the proximal tubules. Interestingly, both DAF and MCP, which inhibit complement activation at C3/C4 level, were not expressed in the apical portion of the tubular cells including proximal tubule brush border. In contrast, HRF20 was expressed on the apical part of the tubules. Medullary interstitium strongly expressed MCP but not DAF. Based on these observations, we conclude that each segment of the kidney is protected from the complement attack by the different combination of complement regulatory proteins. We speculate that the tubular cells might be fragile when complements are activated inside the tubular lumen, because there is no expression of complement regulatory proteins which inhibit C3 convertase.

BACKGROUND: Thrombomodulin (TM), a glycoprotein expressed on the surface of endothelial cells, transforms protein C into a potent anticoagulant by binding thrombin. TM may be an important regulator of intraglomerular coagulation because functional TM activity was demonstrated in glomeruli isolated from normal human and rat kidneys. The role of TM in glomerulonephritis is unknown. EXPERIMENTAL DESIGN: Sections from 4 normal human kidneys and from kidneys of 100 patients with various forms of glomerulonephritis were studied by light and transmission electron microscopy, and by light and electron immunohistochemical techniques using polyclonal antibodies to recombinant human TM, and monoclonal antibodies to the membrane attack complex of the complement system. The expression of TM was graded from 0 to 4 according to the intensity and extent of the distribution, and the results were compared with the clinicopathologic findings. RESULTS: In normal glomeruli and in glomeruli with minimal abnormalities, a small amount of TM was localized at the vascular pole only (grade 0-1). In membranoproliferative glomerulonephritis and lupus glomerulonephritis, the amount of TM found on the plasma membrane of endothelial cells was significantly increased (grades 2 to 4). The expression of TM was directly correlated with proteinuria (p < 0.001), glomerular hypercellularity (p < 0.01), and number of subendothelial immune deposits (p < 0.01). In contrast, in other forms of glomerular diseases, TM was not increased and no correlation was found with the clinicopathologic parameters. CONCLUSIONS: In membranoproliferative glomerulonephritis and lupus glomerulonephritis, the amount of TM expressed by the plasma membranes of glomerular endothelial cells is increased, and this finding is a marker of disease activity. The significance of an increased expression of an endothelial anticoagulant glycoprotein in diseases characterized by pathologic intraglomerular coagulation is unknown, and requires further studies.

BACKGROUND: Interleukin-6 (IL-6) exerts multiple effects on infiltrated inflammatory cells and on structural cells in tissues. We previously reported that IL-6 expression is increased in the area of glomerular and tubular inflammation and tubular atrophy (Lab Invest 65:61, 1991). In the present study, we investigated the expression of IL-6 and HLA molecules in the tubules of patients with renal diseases, and correlate it with the morphological findings. EXPERIMENTAL DESIGN: Specific monoclonal antibodies and indirect immunofluorescence microscopy were used to identify IL-6, HLA-ABC, and -DR molecules, CD-2+ and CD-8+ lymphocytes and macrophages, in renal tissues obtained by biopsy from 41 patients that were divided into three groups on the basis of clinical, functional, and histologic findings. Group 1 included 12 patients with signs of acute renal disease and prevalent acute tubulointerstitial lesions. Group 2 included 19 patients with signs of chronic renal disease and histologic lesions of glomerulo- and tubulointerstitial nephritis. Group 3 included 10 patients that developed an acute renal disease treated with corticosteroids. When the acute symptoms subsided and the renal biopsy was performed, lesions characteristic of chronic tubulointerstitial nephritis were found. RESULTS: IL-6 was localized in all or in some cells of injured proximal tubules, including atrophic tubules. In one-third of specimens, there was more IL-6 in tubular cells than in infiltrated cells. The strongest expression of IL-6, HLA-ABC, and DR molecules was found in group 1, and the weakest in group 3. In the area with tubulointerstitial lesions, tubular IL-6 colocalized with HLA-ABC. Colocalization of IL-6 and HLA-DR was more evident in tubulointerstitial lesions of patients in group 2. In both groups 1 and 2, the distribution of IL-6 was statistically correlated with that of HLA-ABC and with interstitial infiltration of inflammatory cells. In group 2, there was statistical correlation between the expression of IL-6 and HLA-DR. The expression of IL-6 and of HLA molecules decreased in group 3. CONCLUSIONS: These results suggest that tubular IL-6 may be involved in the pathogenesis of tubulointerstitial nephritis.

Serum parathyroid hormone (PTH) levels in 381 hemodialysis patients were determined using 4 different immunoreactive PTH assay systems. The assay systems assessed were PTH-MC (Mitsubishi), HS-PTH (Yamasa), C-PTH (Eiken) and intact-PTH (i-PTH; Mediphysics). The characteristics of the PTH-MC assay, a new assay developed to detect mid-region PTH, were examined and the interrelationships between the 4 PTH assays were analyzed. The range of measurements using the PTH-MC system was very broad (0.1-50ng/ml), and the accuracy of the data was excellent (intra-assay coefficient of variation [CV] 1.5-2.5% and interassay CV 2.0-5.5%). The PTH values determined by the different PTH assays were strongly correlated with each another. When the correlations between the i-PTH and three other assays each were compared in patients whose PTH levels were low (consistent with i-PTH levels of less than 100pg/ml), the PTH-MC assay yielded the highest correlation with i-PTH. Disproportionately higher i-PTH values compared to the values of the other assays were found in some patients in this analysis. As a consequence of the high correlation between i-PTH and PTH-MC at low PTH levels, the PTH-MC system was the least likely to miss these cases. The i-PTH assay reflects the realtime PTH secretory state, however, the values are easily influenced by changes in serum calcium levels. The three other assays reflect the amount of accumulated PTH fragments, therefore, the PTH values determined by these systems should be increased in hemodialysis patients. Based on this characteristic, the early detection of PTH hypersecretory states by these PTH assays is easier than by the i-PTH assay. Some patients in this study had undetectable i-PTH levels, however, the values determined by PTH-MC were within the range of detection. Even the patients with low levels of PTH may develop overt hyperparathyroidism during long-term dialysis. These results suggest that the PTH-MC system is a preferable assay for serial monitoring of these patients, because the measurable range of PTH-MC assay was broad and its accuracy at low PTH levels was superior to the HS-PTH and C-PTH systems.

We studied the long-term outcome of 268 patients suffering from diabetic end-stage renal disease (DM-ESRD) treated with long-term haemodialysis between 1978 and 1991, with special emphasis on visual acuity as well as the heterogeneity of DM-ESRD The 50% patient survival on haemodialysis was 60 months. Visual disturbances were found in 73.1% (392/536) of eyes at the start of haemodialysis. Chronological assess ment of visual acuity demonstrated the stabilization of visual acuity and 87.1% (364/418) of eyes were stable, 4.8% (20/418) were improved, and 8.1% (34/418) were aggravated in the long term respectively. The change of visual acuity was frequently seen in the short term, and rapid shifts of body fluid to correct overhydration induced abrupt changes of glycaemic control as well as retraction of macular oedema. Hence it might be one of the factors affecting rapid change of visual acuity in the short term. Meanwhile, long-term deteri oration of visual acuity resulted from either hyperten sion unresponsive to medical treatment or poor glycaemic control. Some DM-ESRD patients had only background retinopathy at the start of haemodialysis and these were likely to have the nephrosclerotic glomerular lesion. They were old, not nephrotic and had a mild degree of diabetes during the predialysis stage. Thus, DM-ESRD patients seem to have some heterogeneity in their clinical characteristics, and old DM-ESRD patients with only background retinopathy have the appearance of diabetic macroangiopathy rather than microangiopathy. © 1993 European Dialysis and Transplant Association-European Renal Association.

A 54-year-old woman with nephrotic syndrome underwent renal biopsy. By light microscopy, the glomerular capillary lumen was remarkably narrowed because of diffuse accumulation of Periodic acid Shiff (PAS) positive material along the glomerular capillary wall. By electron microscopy, collagenous fibers were observed in the mesangium and subendothelial area. The fibrous material reacted with antibodies against type I and III collagen but not with those against laminin or type IV collagen by an indirect immunofluorescence technique. This case seemed to be a case of collagenofibrotic glomerulonephropathy. © 1993, The Japanese Society of Internal Medicine. All rights reserved.

Experimental glomerulonephritis was induced in rats to investigate the consequence of the antigen-antibody interaction on the surface of glomerular endothelial cells (GENs). A lectin, Lens culinaris hemoagglutinin (LCH), was first planted in the left kidney by isolated perfusion of a left kidney, and then the circulation was reestablished. Rabbit anti-LCH antibodies were injected from the tail vein 3 minutes after the recirculation of the left kidney, and acute glomerulonephritis ensued. Fifteen minutes after the injection, rabbit immunoglobulin G (IgG), rat C3, and LCH were observed exclusively on the surface of GENs. Accumulation of platelets was prominent. Three hours later, the immune deposits were seen in the subendothelial space, and the polymorphonuclear cells were the dominant infiltrate in the glomeruli. Up to the seventh day, immune deposits were seen in the subendothelial space, and the widening of this area was increasingly observed. Fourteen days later, immune deposits containing rat IgG were observed in the subepithelial area, but they were only occasionally seen in the subendothelial space and in the mesangial area. No crescent formation was seen at day 14, but the mesangial area was expanded, with an increased number of cells. The number of nuclei in the cross-section of a glomerulus increased after the induction of glomerulonephritis, but the number of leukocyte common antigen-positive cells (infiltrating cells) decreased gradually from day 4 to day 14. The staining of Thy-1.1, a marker of mesangial cell, was markedly enlarged in the glomerulus at day 14. These data suggest that mesangial proliferative glomerulonephritis can be induced by the antigen-antibody interaction on the surface of GENs. © 1993.

We describe the development of acute renal failure and degenerative tubular lesions associated with local immune deposits in a patient with allogeneic bone marrow transplantation. A 21-year-old man with an acute myelocytic leukemia received a bone marrow graft from a cousin mismatched for a single HLA-DR locus antigen. Hemorrhagic cystitis due to adenovirus type 11 infection occurred 26 days after transplantation, and 17 days later the patient developed acute renal failure. A study of renal tissue obtained by needle biopsy showed degenerative and necrotic lesions, especially in the distal part of the nephron. By electron microscopy adenovirus type 11 particles were found in the nuclei of tubular cells and in cellular debris in tubular lumina. By immunofluorescence technique, granular immune deposits containing adenovirus type 11 related antigen(s), immunoglobulins, C3, and membrane attack complex (MAC) C5b-9 of the complement system were detected along the tubular basement membranes but not in glomeruli. The patient's IgG did not bind to normal human kidneys. These findings suggest that adenovirus type 11 directly induced acute tubular damage, and that the tubular immune deposits were formed "in situ" by viral antigens and circulating viral antibody. © 1993 by Williams &amp Wilkins.

From 1979 to 1991, 13 cases of pregnancy-related acute renal failure (PR-ARF) were treated in our hospital (7.6% of the total number of acute renal failure needing dialysis). The original diseases causing PR-ARF consisted of diverse disease entities such as: acutè fatty liver of pregnancy (3), postpartum hemolytic uremic syndrome (2), placenta previa (2), abruptio placenta (1), ectopic pregnancy (1), septic abortion (1), atonic bleeding (1), cervical laceration (1) and delayed delivery (1). Maternal mortality was 23% (3/13), which compares favorably with other causes of ARF. The cases who developed PR-ARF in recent years recovered normal renal function. Those who died tended to be earlier cases in this study and all suffered acute cortical necrosis (ACN). According to histological diagnosis, the prognosis of ACN was the worst, whereas those who suffered postpartum hemolytic uremic syndrome as well as acute tubular necrosis recovered renal function completely. There was a statistically significant difference in the number of disturbed organs between survivors and the deceased. Thus, multiple organ failure accompanied with massive hemorrhage possibly plays a critical role affecting patient survival. New devices for dialysis treatment, plasmapheresis and better control of hemorrhagic diathesis have gradually improved the survival rates in our institutes. Plasmapheresis was effective in the treatment of postpartum hemolytic uremic syndrome as well as acute fatty liver of pregnancy. Though improvements in obstetric care have resulted in a dramatic decline in the incidence of PR-ARF, obtaining a better prognosis for PR-ARF is an important task for us since PR-ARF is likely to occur in the young generation. In conclusion, better control of hemorrhagic diathesis as well as the technological progress of dialysis treatment has improved the prognosis of PR-ARF, however, more effort is needed if full survival is to be accomplished.

Kidneys of Balb/c mice intravenously injected with rabbit antibodies to heparan sulfate proteoglycan (HSPG) derived from PYS-2 cells were studied for 14 weeks. Antibodies were found to bind to the glomerular basement membrane (GBM) as early as 15 min after the injection. Binding of antibodies was observed over the whole thickness of the GBM. The lamina rara interna and foot process base appeared to be more intensely stained. This pattern did not change throughout the experiments. Mild inflammatory changes (infiltration of polymorphonuclear cells and swelling of the glomerular endothelium) were seen at the initial stage (~1 day), and mesangial expansion followed (1–4 weeks). In mice pre- and booster-immunized with normal rabbit IgG, a moderate autologous response was observed by immunofluorescence microscopy, but no significant inflammatory changes were noted. At the late stage (6 weeks ~), irregular GBM thickening was observed. The thickening was due mainly to expansion of the lamina rara externa. These findings suggest that the anti-HSPG antibodies caused mild glomerulonephritis at the initial stage, and later caused thickening of the GBM possibly by disturbing the assembly, production and degradation of GBM components. © 1989, Japanese Society of Nephrology. All rights reserved.

Diabetic nephropathy is the second most frequent underlying disease among patients on hemodialysis. In order to elucidate the deleterious factors affecting the decline in renal function in diabetic nephropathy, and to clarify the beneficial effects of dietary treatment, retrospective analysis was done using Δ1/creatinine regression analysis. It was revealed that the amount of urinary protein has a deleterious effect on the deterioration of renal function, while a protein-restricted diet has a favorable effect. Also, it was considered that diabetic nephropathy has a heterogeneous character, and that aged patients who show low-grade proteinuria, mild ocular lesions and have not undergone insulin treatment have lesions of a nephrosclerotic rather than a diabetic nephropathic character. The improvement of overhydration by hemodialysis treatment induced aggravation of diabetic control. Therefore anasarca is considered to contribute to the amelioration of diabetic status, which is frequently observed at the end-stage of renal failure.

The nutritional assessment in hemodialyzed patients is a still important problem although remarkable development of hemodialysic technique has been achieved. To assess the nutritional status of these patients, we made this survey by the method with dietetic interviews and diaries, urea nitrogen appearance (UNA) study, anthropometry, evaluation of the degree in social rehabilitation, and the measurement of serum protein (alubumin, transferrin, cholinesterase, C₃). The results of UNA study showed a close relationship to dietetic diaries in spite of mass study, and raised both the objectivity and authenticity. Certain anthropometric measurements were abnormal in the greater part of patients in the following parameters such as % relative body weight, skinfold thickness and mid-arm muscular circumference. From the synthetic evaluation of these measurements, the most patients remaind still malnutritioned, and it was suggested that they might intake a lowenergy diet. Meanwhile, 1.2 g of protein per kilogram of body weight is a sufficient dose for prescription. The low phosphorus diet cannot recommended at present, because it may force low protein diet to patients.

Screening urinalysis of 89, 137 (72.4%) out of 123, 148 students in Nagoya University were carried out from 1972 to 1985. The percentage of proteinturia and hematuria were 5.4% and 1.1% respectively at screening test. Renal biopsy was performed in 98 students with chance proteinuria and/or hematuria. The following results were obtained. Minor glomerular abnormalities were shown on the renal specimens in 50.0% of biopsied cases on light microscope. Group of isolated hematuria had the mildest histological finding, comparing with group of proteinuria alone and that of both hematuria and proteinuria. Moreover, group of proteinuria alone showed milder histological changes than that of both hematuria and proteinuria. Immunonuorescent study was carried out in 49 cases. IgA nephropathy accounted for 44.9% of these cases. © 1987, Japanese Society of Nephrology. All rights reserved.