We have observed that long-term saline load significantly suppressed the development of acute renal failure (ARF) in glycerol-induced acute renal failure rats, and that the reductions in renal blood flow and total hepatic blood flow were significantly less in saline-loaded rats. When rats which had recovered from glycerol-induced ARF (recovery rats) were rechallenged with glycerol, the development of ARF was also significantly suppressed. In order to study this process, we estimated the systemic hemodynamics in recovery rats using the microsphere method. As a result, cardiac output, total hepatic blood flow and renal blood flow after intramuscular injection of glycerol decreased significantly less in recovery rats compared to control rats, and % of cardiac output to the kidney 4 hours after glycerol injection was significantly higher than pretreatment levels only in recovery rats. These results suggested that the maintenance of not only renal blood flow but also hepatic blood flow, specifically observed in recovery rats rechallenged with glycerol, are important factors in suppressing the development of ARF in recovery rats.

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The present study is an attempt to elucidate the vulnerability of focal glomerular sclerosis (FGS). This phenomenon is considered that is due to the difference of morphology and function of individual glomeruli among the subcapsular cortex, the juxtamedullary cortex and column of Bertin (CB). We investigated the mesurement of inside diameter of afferent arterioles (Aff) and efferent arterioles (Eff) by the scanning electron micrographs (SEM) of methyl methacrylate casts of intrarenal arteries and also an aspect of arterial cushions are examined. The object of this study was performed on 3 autopsied kidneys without renal disease. The results of the mesurement of inside diameter of both arterioles, Aff of glomeruli were larger than Eff distributed in the subcapsular cortex, and were similar to the glomeruli in the middle portion of CB. Nevertheless Eff of the juxtamedullary glomeruli were nearly equal or larger than Aff, statistically (t-test). Furthermore, standard diviation of the numerical value of Eff were seen with larger variation. The glomeruli in parapyramidical portion of CB show a similar tendency to juxtamedullary ones. A structure of "arterial cushions" were observed on the wall of intralobular artery at the portion of bifurcation to afferent arterioles in juxtamedullary cortex. These cushions show elongated indentation surrounding lumen of the arterioles. The results of these examination, it was supposed that hemodynamics and function of the glomeruli located in subcapsular cortex and middle portion of CB are similar situation, and also juxtamedullary cortex bear resemblance to parapyramidical portion of CB. The disorder of autoregulation of interlobular artery due to dysfunction of arterial cushions with anionic loss were assumed to be a factor in progress to glomerular sclerosis.

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In an attempt to elucidate characteristics of the clinical courses in crescentic glomerulonephritis (Cres. GN), reciprocals of serum creatinine concentration (1/Cr) with time were studied in 18 patients. They fulfilled the following criteria; 1) crescents were observed in more than 50% of glomeruli, and 2) serum Cr was determined sequentially three or more times since their first examinations, when Cr was documented to be 2.0 mg/dl or less, In all patients 1/Cr declined linearly with time with the correlation coefficient of 0.881 to 0.993. According to the declination rate, the patients were divided into two groups; one was an acute type (10 patients) with the rate of -1.0×10^-2 dl/mg/day or less, and the other was a subacute type (8 patients) of more than -1.0×10^-2 dl/mg/ day. Histologically, there was no difference in percentages of glomeruli with crescents between the two groups. However, in the acute type cellular crescents were observed predominantly, and a negative correlation between periods from the onset of the disease to the time of renal biopsy and percentages of glomeruli with cellular crescents was ob-served (r=-0.902, p<0.01). Endocapillary proliferation was also more frequent in the acute type (p<0.05). On the contrary, in the subacute type crescents in various phases were observed. As for their prognosis, Cr improved to 1.2 mg/dl or less in 5 of the acute type and hemodialysis was discontinued in another patient. On the contrary, 6 patients of the subacute type died of renal failure or were tranferred to chronic hemodialysis and the other two remained in azotemia. Conclusively, according to the declination rate of 1/Cr, Cres. GN could be divided into acute and subacute types; the former may follow a favourable clinical course in spite of rapid deterioration of renal function in the initial phase, but the latter may show slow but steady deterioration of renal function.

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Since activation of the complement system was shown to be initially operative in acute poststreptococcal glomerulonephritis (APGN), we assessed the presence of MAC in kidney tissue from patients with APGN using a monoclonal antibody (courtesy Dr. A. F. Michael). Renal tissue from 30 patients with APGN were obtained 1-44 days after onset of disease. Cryostat sections were examined for the presence of MAC. Specimens from 150 patients with various renal diseases (MN, MPGN, IgA GN, Non IgA GN, MCNS, FGS, SLE) were also examined. In APGN almost all specimens showed intense peripheral staining for MAC, C3, C5, C9 and P in the glomeruli, while staining for immunoglobulins and early components were weak and not constant. These results suggest that activation via the alternative pathway leads to abundant MAC formation in APGN. Glomerular deposition of MAC were still observed in rebiopsied cases. Among various renal diseases glomerular deposition of MAC was frequently found in MN, MPGN, IgA GN and SLE. The staining pattern was characteristic of each disease groups. In all disease groups the staining for MAC, C5 and C9 was similar to that of C3, but MAC and late components tended to deposit in the vessel walls and TBM without notable C3 deposition. MAC seems to exist in tissues in the form of SC5b-9, because MAC and S protein were always colocalized in all loci. There was no apparent correlation between MAC deposition and proteinuria in APGN, IgA GN and SLE. Further investigations are necessary to determine the biological activities of MAC deposition in renal tissue.

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It is reported that blood urea nitrogen (BUN) rises up logarithmically with advancement of renal dysfunction, and serum guanidinosuccinic acid (s-GSA) rises in parallel with BUN, but there is no mention about the rising pattern of s-GSA during the course of CRF. In order to investigate the significance a rising pattern of s-GSA in relation to the progression of renal damage, we measured serum creatinine (s-Cr), BUN, and s-GSA in 79 patients with CRF due to chronic nephritis or polycystic kidney disease recieving conservative therapy. The paramater of renal function, we use the reciprocal of s-Cr(1/Cr). The logBUN was significantly in negative proportion to 1/Cr (logBUN=-1.33×1/Cr+2.21 r=-0.845 p<0.01 n=69). The correlation between BUN and logGSA was also significant (logGSA =0.012×BUN+1.50 r=0.801 p<0.001 n=69), and the relationship between logGSA and 1/Cr was in negative proportion (logGSA=-2.81×1/CrH-2.97 r=-0.772 p<0.001 n=78). These results suggest that in which 1/Cr remains relatively high, the rising rate of s-GSA was lower than that of BUN, but as the renal damage advanced to the critical state of renal failure, in which 1/Cr approached a critically low level, rising rate of s-GSA became abruptly higher than that of the BUN. The s-GSA is a more sensitive marker of the changes of renal function in the critical period of CRF.

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Diabetic nephropathy, which is considered to be as significantly on the prognosis of diabetes, is usually diagnosed on clinical grounds. In the present study we have measured urinary albumin excretion rates (AER) using immunological assay in seventy non-insulin-dependent patients with diabetes mellitus whose Albustix tests were negative, in order to investigate the possibility of early detection of diabetic nephropathy and to establish a starting period for therapy. The relationships between AER and onset of retinopathy, HbA1c, duration of diabetes and blood pressure were also examined. 1). Diabetics showed significantly higher values of AER than controls, both after a period of bed rest and immediately upon arrival at the outpatients clinic (without rest). In diabetics, AER was significantly higher on arrival at the clinic than after bed rest. 2). A higher proportion of individuals with retinopathic complication suggesting a progression to microangiopathy was observed among those whose AER was 30 μg/min after bed rest or 60μg/min without rest than those showing 15μg/min after bed rest or 30 μg/min without rest. 3). AER showed higher value with longer duration of diabetes and higher HbA1c titer. 4). Patients with a mean blood pressure of less than 100 mmHg showed a higher value of A ER than those with from 100 to 115 mmHg. The above findings indicate that therapy for diabetic nephropathy should be initiated when AER has shown more than 15 μg/min after bed rest or more than 30 μg/min without rest on at least two separate occasions. The control of HbA1c and blood pressure is important in prevention of microangiopathy.

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Three patients with breast cancer (Adenocarcinoma) were treated with MMC and 5FU. During the course of the treatment mesangial proliferative glomerulonephritis was developed in the all of the patients and they were associated with microangiopathic hemolytic anemia (MAHA) 4 to 7 months after the beginning of the chemotherapy. The complications, in the two cases improved spontaneously, but one died with cardiac tamponade 14 months after the first administration of MMC. Histological observation in biopsied kidney revealed mesangial proliferation with lobulation and partial thickening and/or splitting of BM. Electronmicroscopically, widening of subepithelial spaces and accumulation of nonhomogenous materials in subendothelial spaces were observed. No deposition of immunoglobulins and complement components were observed by immunofluorescence.

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Attempting to clarify morphogenesis of diabetic nodular lesions, fresh frozen and paraffine embedded kidney specimens obtained from 38 diabetic patients were comparatively observed using serial sections treated for light (PAM stain) and immunofluorescence (monoclonal antibodies against type III, IV and VI collagens) microscopies. Type III collagen was detected in the glomerular vascular pole and interstitium, type IV and type VI collagens in the mesangium and glomerular capillary walls, and, additionally, the former along the Bowman's capsule and tubular basement membrane, and the latter in the interstitium. The diabetic diffuse lesion, which was strongly positive for PAM stain was re-active to both anti-type IV and VI collagen antibodies. As for the nodular lesion, the core portion of the lesion, which might be a sequela of mesangial stalk, was strongly PAM-positive, but the surrounding concentrically laminated acellular area was weakly positive. By comparative observations, type IV collagen was mainly detected in the strongly PAM-positive area, and type VI collagen in the weakly positive area, but type III collagen was not detected in these lesions. In some cases, the portion corresponding to the laminated area was structureless, but had the same histochemical and immunological properties as the laminated area. In addition, this nodule-like lesion showed various intermediate forms from the diabetic mesangiolysis to the nodular lesion. These results suggest that the laminated diabetic nodular lesion was not formed by expansion of the mesangial area, but by an increase in type VI collagen in the reconstructive process of the diabetic mesangiolysis.

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It is currently accepted that serum uric acid concentration correlates with the severity of preeclampsia. However, although the average serum uric acid concentration of preeclampsia showed significant increase compared to that of normal pregnancy (p<0.01), in the individual cases, this index failed to differenciate preeclampsia from normal pregnancy. On the other hand, these two conditions were clearly distinguished by uric acid clearance that was determined by 24 hour urine sample. The uric acid clearance showed significantly positive correlation with baby's birth weight (r=0.81, p<0.05) and negative correlation with mean blood pressure (r=-0.84, p<0.01). Uric acid clearance also significantly increased in superimposed preeclampsia compared to normal pregnancy with chronic glomerulonephritis (p<0.01) and there was no overlap between these two groups. From these results, we postulate that uric acid clearance is one of the most reliable indices not only to diagnose and estimate the severity of preeclampsia but also to differenciate normal pregnancy with glomerulonephritis from superimposed preeclampsia.

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We determined acid phosphatase and also studied the elution pattern of the enzyme in urine from patients with various renal diseases. Patients with IgA nephropathy, nephrotic syndrome, acute pyelonephritis, and Alport's syndrome had significant enzymuria compared to normal controls. Patients with nephrotic syndrome also showed substantial enzymuria even in clinical remission. On chromatography, acid phosphatase in urine was separated into 4 components. Acid phosphatase isoenzyme 1 and isoenzyme 4 significantly increased in urine from patients with IgA nephropathy and nephrotic syndrome. Patients with Alport's syndrome showed a characteristic elution pattern. Despite high activity of acid phosphatase isoenzyme 1 and isoenzyme 4, acid phosphatase isoenzyme 2 or isoenzyme 3 was not detectable in urine of Alport patients. Acid phosphatase assays may be helpful in diagnosing Alport's syndrome.

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In this study the long-term graft function of 62 kidney transplant patients treated with ciclosporin (CYA) was investigated and the factors influencing the outcomes were assessed. CYA was initiated at an oral dose of 12 mg/kg/day and the dose was gradually tapered based on CYA serum trough level. Serum creatinine (S-Cr.) level increased with time and the level at 3 years was 2.13±0.78 mg/dl in living cases and 2.07±1.17 mg/dl in cadaver cases. These levels in the CYA group were significantly higher than those in the conventional group. No relationship between the S-Cr. levels and the dose of CYA and the immunosuppressive regimens was found at 3 years after transplantation. Rather, the 3-year S-Cr, levels were related to events soon after transplantation. The frequency of acute rejection within 3 months in the low S-Cr. (<1.5 mg/dl) group (35%) was rather low compared with that in the high S-Cr. (1.5 mg/dl<) group (64%). In addition, CYA nephrotoxicity (CYA-NT) was more frequently recognized by biopsy in the high S-Cr. group than in the low S-Cr. group. Concerning CYA-NT, chronic NT especially influenced long-term graft function. In the low S-Cr. group, the total doses of CYA in the early stage (1, 3, 6 months) were smaller than those of the high S-Cr. group. These data indicate that it is important to avoid acute rejection and CYA-NT, especially chronic CYA-NT in order to maintain good long-term graft function. Therefore, immunosuppression using a low dose of CYA in combination with other drugs (triple or quadruple therapy) is recommended just after transplantation.

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One hundred eighty graft biopsy specimens of 133 patients with elevated serum creatinine concentrations were studied and the impairment of graft function was assessed in kidney transplant patients treated with ciclosporin (CYA). Of 180 graft biopsies, 68 were obtained during the first month, 37 from 2 to 6 months, 21 from 7 to 12 months, 32 from 1 to 2 years, 22 from 2 to 4 years after transplantation. In the first 6 months acute rejection was observed in 50% of the specimens and acute CYA nephrotoxicity (CYA-NT) in 30%. Between 7 and 12 months chronic rejection appeared in 28% and chronic CYA-NT in 24%. Between 1 and 2 years the specimens showed basically the same findings as did those between 7 and 12 months. Between 2 and 4 years 55% of the specimens displayed chronic CYA-NT and chronic rejection was observed in 23%. In this way, graft dysfunction was considerably related to acute or chronic CYA-NT at various posttransplant points. Acute CYA-NT contributed to 30% of graft dysfunction in the early stages and was related to high CYA serum trough levels (244±86ng/ml). On the other hand, chronic CYA-NT contributed to 20% of graft dysfunction from 7 months to 2 years and 55% of that after 2 years. In addition, chronic CYA-NT was observed at low CYA serum trough levels (94±37ng/ml). However, in most of the patients with chronic CYA-NT, CYAA serum trough levels within 3 months were found to have been high (>300 ng/ml). In conclusion, CYA-NT considerably influenced graft function in all stages after transplantation. Acute CYA-NT developed in patients with high CYA levels within 4 months end chronic CYA-NT appeared after 6 months and was associated with high CYA levels within the first 3 months. Therefore, treatment in the early stages with a low dose of CYA in combination with other immunosuppressants is recommended in order to minimize he impairment of long-term graft function.

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A 41 year-old man was admitted to our hospital with complaints of general fatigue and macroscopic hematuria. About 3 months ago, a health check revealed proteinuria and hematuria, and renal insufficiency progressed rapidly. On admission, laboratory evaluation revealed a BUN of 57 mg/dl ; serum creatinine 6.9 mg/dl; hemoglobin 10.8 g/dl; erythrocyte sedimentation rate 132 mm/hr. On the 6th day after admission, dyspnea and hemoptysis occurred suddenly, and chest X-ray showed evidence of bilateral diffuse intraalveolar hemorrhage. A percutaneous renal biopsy specimen showed diffuse crescentic glomerulonephritis. Direct immunofluorescence studies showed strong linear staining for immunoglobulin G (IgG) along the glomerular capillary walls. Using the indirect immunofluorescence technique, we could confirm the presence of an anti-glomerular basement membrane antibody (anti-GBM antibody) which bound to normal kidneys not only in the serum of the patient but also in the eluate of the renal biopsy specimen. From the next day of hemoptysis, the patient underwent plasma exchange of 3 liters, 16 times combined with large doses of methyl-prednisolone administered intravenously as "semi-pulses" followed by oral administration of prednisolone and cyclophosphamide. Soon after treatment began, the patient had shown improvement symptomatically and has had no further pulmonary problems, but he has remained oliguric requiring hemodialysis 3 times a week. We concluded that in the patients with Goodpasture's syndrome, intensive therapy is effective in terminating serious life-threatening pulmonary hemorrhage particularly when undertaken early even when renal failure was irreversible.

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Glomerular permeability and change in anionic sites in aminonucleoside nephritis were investigated using thirty-six rats. The rats were studied for 14 days after receiving a single intraperitoneal injection of aminonucleoside 25 mg or 50 mg/200g·BW. The rats injected with aminonucleoside 25 mg/200g·BW were administered heparin 400 U/200g·BW, dipyridamole 20 mg/200 g·BW and prednisolone 1 mg/200 g·BW intraperitoneally for ten days, and were sacrificed 14 days after the aminonucleoside injection. The mean proteinuria in the control rats was 3.5±0.8 mg/day, and the anionic sites were distributed at regular intervals in the lamina rara externa with a frequency of 17.7±0.5/1000 nm GBM. Histological observation of the kidneys taken from rats with proteinuria induced by 25 mg/200 g ·BW aminonucleoside revealed partial loss of the anionic sites from the GBM, although complete fusion of the foot processes was not noted. The maximum proteinuria in the 50 mg/200 g·BW aminonucleoside-injected rats was 348.4±45.3 mg/day. The anionic sites in the lamina rara externa were markedly reduced to 1.0±0.5/1000 nm GBM, and were irregularly located in the GBM, which itself was irregularly thickened. Animals injected with heparin 400 U/200 g·BW after receiving 25 mg/200 g BW aminonucleoside indicated a markedly increased number of anionic sites, 13.1±2.4/100 nm GBM, and a reduction in proteinuria, although fusion of the foot processes remained. The anionic sites observed in rats given dipyridamole 20 mg/200 g BW after receiving aminonucleoside 25 mg/200 g·BW were regulary distributed within the lamina rara externa, with 15.7±1. 2/1000 nm GBM, markedly reduced proteinuria, and moderate fusion of foot processes notable. Rats injected with 1 mg/200 g·BW prednisolon after received aminonucleoside of 25 mg/ 200 g BW exhibited noticeably reduced proteinuria, and regularly distributed anionic sites within the lamina rara externa, with 11.1±1.5/1000 am GBM and destruction of the foot processes and mesangial proliferation being relatively severe. We concluded that the reduction of the anionic sites in the renal GBM induced an increase in proteinuria in the aminonucleoside-induced nephritic rats.

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The late components of complement, C5b through C9 constitute membrane attack complex (MAC). Using a monoclonal antibody to a neoantigen expressed on MAC, we localized MAC in the tissue sections from normal kidneys and biopsy specimens from patients with a variety of kidney diseases. In the normal kidneys, MAC was present in a granular pattern along the segments of tubular basement membrane (TBM) and the wall of blood vessels, and weakly in the glomerular mesangium. MAC deposition was observed in the mesangial area and along the glomerular capillary walls of patients with IgA nephropathy, Henoch-Schonlein purpura nephritis, lupus nephritis, membranous nephropathy and membranoproliferative glomerulonephritis. The MAC was frequently co-deposited with C3 and IgG or IgA, suggesting MAC was formed in situ and associated with immune deposits. In patients with oligomeganephronia and hemolytic uremic syndrome, mesangial MAC deposition was generally dissociated with C3 or immunoglobulins, implying that MAC was entrapped from the circulation. In IgA nephropathy, there was no correlation between glomerular MAC deposition and clinical findings of the patients, i. e. renal function, proteinuria or renal histology.

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