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Inulin clearance (Cin) is widely believed to be the gold standard of the glomerular filtration rate (GFR). However, in Japan, Cin has not been officially recognized by the Ministry of Health, Labour and Welfare of Japan for clinical use. Creatinine clearance (Ccr) has been used to estimate the renal function of patients, but there have been many studies in which Ccr estimates were GFR falsely high because the metabolism and tubular excretion of creatinine widely varied according to the pathophysiological state of the patient. In the present study, we determined Cin and Ccr simultaneously in 116 adult patients with renal diseases and diabetic mellitus. The clearance study was performed by the modified Wesson's method. The inulin preparation was FFI-1010 (Fuji Yakuhin Co. Ltd.). Inulin in serum and urine was determined by the newly devised enzymatic assay (Toyobo Co. Ltd.), which is specific for inulin. The mean Cin was 35.0 +/- 14.4 ml/min/1.73 m2. The mean Ccr(the enzyme assay) was 63.6 +/- 24.1 ml/min/1.73 m2 and that of the kinetic Jaffe assay was 55.3 +/- 19.3 ml/min/1.73 m2. Mean Ccr/Cin was 1.93 +/- 0.73, 1.69 +/- 0.62, respectively. This ratio was significantly different(p < 0.05) in the degree of reduction of Cin, with values of 2.07 +/- 0.82 (Cin < 40 ml/min/1.73 m2) and 1.64 +/- 0.32(40 < Cin < 80 ml/min/1.73 m2), respectively. Only 8 patients were classified into the same degree of reduced renal function (the Guideline of Japanese Society of Nephrology). The findings of this study suggest that the GFR determined by Ccr could misjudge the renal function of patient and delay the administration of proper treatment of the patient. Introduction of Cin into the clinical field is necessary to avoid this delay.

Overproduction of transforming growth factor-beta 1 (TGF-beta 1) has been implicated in the pathogenesis of fibrotic diseases. TGF-beta 1 plays a crucial role in the accumulation of extracellular matrix (ECM) in human and experimental glomerular diseases. However, it remains unclear whether inhibition of TGF-beta 1 overproduction would suppress TGF-beta 1-induced ECM accumulation. To inhibit the overproduction of TGF-beta 1 in experimental glomerulonephritis induced by anti-Thy 1.1 antibody, we introduced antisense oligodeoxynucleotides (ODN) for TGF-beta 1 into the nephritic kidney by the HVJ-liposome-mediated gene transfer method. Sense, scrambled or reverse ODN were also introduced as controls. Transfected ODN accumulated mainly in the nuclei of mesangial cells in the glomeruli of transfected kidneys. In the antisense ODN-transfected rats, a marked decrease in expression of TGF-beta 1 mRNA was confirmed by Northern analysis. Consequently, the expression of TGF-beta 1 protein in the glomerulus was markedly reduced in the antisense ODN-transfected kidney with a comparable effect in preventing glomerular ECM expansion in experimental glomerulonephritis. In contrast, sense, scrambled and reverse ODNs failed to suppress TGF-beta 1 expression and ECM accumulation. Thus, these results suggested that inhibition of TGF-beta 1 overproduction could suppress progression to glomerulosclerosis.

To determine factors mediating the aldosterone secretory response to orthostasis, we examined the effect of angiotensin-converting enzyme inhibition (CEI) on orthostasis in eight normal subjects and 10 normotensive patients with primary glomerulonephritis ingesting a normal sodium intake. On standing with CEI, the mean plasma aldosterone concentration (PAC) did not change [68.6 +/- 3.9 (+/- SE) and 63.4 +/- 6.9 pg/ml] in normal subjects, while PAC rose significantly from 72.3 +/- 7.5 to 129.5 +/- 13.2 pg/ml (P less than 0.001) in the glomerulonephritis patients without a concurrent rise in plasma angiotensin II, serum potassium, plasma ACTH, or mean blood pressure. There was a good correlation (r = -0.7064; P less than 0.03) between the changes in PAC and the changes in fractional sodium excretion in the patients. Pretreatment with indomethacin blunted the rise in PAC from 159.0 +/- 21.5 to 63.3 +/- 10.2 pg/ml upon standing with CEI, without a concurrent change in circulating 6-keto prostaglandin F1 alpha (from 57.7 +/- 9.5 to 56.0 +/- 11.1 pg/ml) in 4 patients. These results suggest that the aldosterone secretory response to orthostasis in patients with glomerulonephritis is dependent on factors blunted by pretreatment with indomethacin in addition to angiotensin II.

During investigation of chronic glomerulonephritis, a 24-year-old man was found to have a low serum urate concentration (0.6-1.3 mg/100 ml). Daily urinary excretion of urate and oxypurines was normal. His urate clearance was markedly increased (43.3-98.0 ml/min), and was substantially unchanged after both the administration of pyrazinamide, an inhibitor of the renal tubular secretion of uric acid, and the administration of probenecid, an inhibitor of the renal tubular reabsorption of uric acid. No other renal tubular abnormalities were detected. It was concluded that the patient had an isolated defect in the renal tubular reabsorption of uric acid. The patient's brother was also found to have hypouricemia due to renal uricosuria, suggesting a genetic origin of the defect.

Immunofluorescent staining of urinary casts of patients with chronic glomerulonephritis or with acute renal failure was performed. Urinary and cast Tamm-Horsfall mucoproteins were purified by a modified McQueen's method. Rabbits were immunized by both of these materials to obtain antisera. The antigenic specificity of the prepared material was examined by Ouchterlony gel diffusion method and immunoelectrophoresis. Indirect and direct immunofluorescent staining methods were done using Tamm-Horsfall mucoprotein antiserum and FITC-GARG, FITC-labelled IgG, IgA, IgM, C3 and albumin. Hyaline casts of both chronic glomerulonephritis and acute renal failure demonstrated fluorescence with Tamm-Horsfall mucoprotein antiserum. The nature of the granular casts of chronic glomerulonephritis seemed to be different from those of acute renal failure because the granules of the former fluoresced for some serum protein fractions, but the latter fluoresced only for Tamm-Horsfall mucoprotein. The absence of fluorescence with epithelial casts for any serum protein fractions implied a different pathogenesis for epithelial casts as compared to granular casts, contrary to Lippman's assumption. A routine technique of immunofluorescent staining of urinary casts was developed. The interpretation of urinary casts should be more specific by this new technique.

The effects of administration of angiotensin II (ANG II) and antidiuretic hormone (ADH) on the glomerular filtration rate (GFR, measured as creatinine clearance) were examined in patients with mesangial proliferation. For this study, the patients whose conditions were similar to that of healthy subjects, except for asymptomatic urinary abnormalities and glomerular histological changes, were selected. Both ANG II and ADH administration significantly decreased GFR in the patients and the healthy subjects. Compared to the healthy subjects, a significantly greater drop in GFR was observed in the patients following ANG II infusion with or without SQ14225 administration, but not following ADH infusion. We conclude that mesangial proliferation may modulate an ANG II induced drop in GFR.

The prognosis of chronic glomerulonephritis based on renal function was assessed using a statistical technique of the Markov process, where the absorbing state was assumed to be an uremic state, 194 adult patients with different types of disease were subjected to study. The 15 min value obtained in the intravenous PSP excretion test was divided into five states; SI (greater than 34%, normal), SII(25-34), SIII(15-24), SIV(5-14) and SV (greater than 5, uremic). The rates of SV with time were calculated with respect to several clinical characteristics. The prognosis of the patients with hypertension, distinct proteinuria and hematuria, or cellular cylindruria appeared to be relatively poor. The estimated number of years from each state to SV were also calculated. The results were similar to those already reported and gave us more exact information about the prognosis.

The effect of the change from supine to upright position on GFR (measured by creatinine clearance) was studied in nonazotemic patients with biopsy-proven primary glomerulonephritis. Compared to healthy subjects, the fall in GFR following the postural change was significantly larger in patients with mesangial proliferation (MP) and with both MP and thickening of glomerular capillary wall (GCW), while similar in those with thickening of GCW alone, suggesting that MP, but not thickening of GCW, augments posturally induced fall in GFR. The augmented fall in GFR in patients with MP was accompanied by larger fall in GFR per unit increase in plasma renin activity than in healthy subjects, and was eliminated by angiotensin-converting enzyme inhibition. We conclude that MP augments posturally induced fall in GFR through affecting glomerular reactivity to angiotensin II.

Incidence of hypertension in chronic glomerulonephritis and its influence on the clinical course of the disease were studied using statistic technique, especially that of Markovian process. 1. Incidence of hypertension in a total of 283 cases was 15.2%, while in the patients of which renal function reduced to approximately one half of the normal was about 50%. 2. The average of blood pressure in this disease tends to elevate with the decrease in 15 minute value of PSP excretion test and with the increasing serum creatinine level, although the variations are large. 3. After a fall of renal function to approximately one-third of the normal, the rate of clinical course is markedly rapid. 4. The prognosis of the progressive type of chronic glomerulonephritis is obviously affected to be shorten by the presence of hypertension. 5. According to the results obtained by the Markovian approach, survival years of the patients with wide range of renal function can be predicted with relative accuracy.