In this Editorial we shall try to show the benefit that could bring a new approach of glomerular pathology that is biochemical studies of isolated glomeruli and cultivated glomerular cells. We shall successively consider the principal biochemical activities of the isolated glomerulus and three precise areas in which biochemical alterations within the isolated glomerulus could play a role : spontaneously reversible acute renal failure, experimental diffuse proliferative glomerulonephritis, chronic rejection of human kidney transplant. We selected these examples for they were studied at Hôpital TENON, Paris, where are gathered three different units of clinical nephrology, experimental pathology and investigative physiology. We are aware that this presentation is too restricted as it does not take into account what was done in the few other research laboratories directly involved in same field. Indeed M. Dunn in Cleveland, T.P. Dousa in Rochester and Y. Orita in Professor Abe's Department in Osaka are the other investigators who followed with their groups the same approach, maybe more physiologically oriented.

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Histopathological examinations of kidney specimens from 25 patients with MCLS were carried out to clarify the details of the renal involvement. Vascular lesions such as panarteritis with extensive necrosis, arteriolitis, phlebitis, thromboarteritis with infarcts, and intimal proliferative occlusive arteritis were observed in some male infants, in whom the duration of illness was short. Glomerular hypercellularity with a small number of crescents and/ot fibrosed glomeruli was often found. Cell infiltration in the interstitium and WBC and WBC casts in dilated tubules were remarkable. Some vasculitis, hypercellularity in glomeruli and interstitial cell infiltration were characteristic of the kidney in some fatal cases of MCLS, a systemic vascular disease. In general, the renal lesions in MCLS were milder than in infantile polyarteritis nodosa (IPN) and no fibrinoid necrosis in the arteries and glomeruli was observed.

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A comprehensive study on immunological abnormalities in family members of patients with IgA nephropathy was made to determine whether there are any familial factors in the development of this disease. The serum IgA levels, amounts of IgA bearing cells, T cells with Fc receptor for IgA (Tα cells) and B cells with Fc receptor for IgA (Bα cells) as well as spontaneous IgA synthesis by peripheral blood mononuclear cells, were examined in the patients and their family members. Serum IgA levels were measured by single radial immunodiffusion. The amounts of IgA bearing cells, Tα cells and Bα cells were estimated by flow cytometry using the FITC-conjugated F (ab')₂ portion of antihuman IgA and FITC-conjugated IgA myeloma protein. Spontaneous lgA synthesis was examined in culture supernatants of peripheral blood mononuclear cells by solid phase immunofluorescence assay. The amounts of IgA bearing cells were significantly increased in both the patients with IgA nephropathy and their family members. The serum IgA levels and Ba cells were significantly increased in the patients and some of the family members, but the increase in the latter was not statistically significant. Spontaneous IgA synthesis was significantly increased in family members as well as in patients. Some of the patients and family members revealed increased amounts of Tα cells but they were not statistically significant. It is concluded that IgA production is enhanced in family members of patients with IgA nephropathy. It is postulated that familial high responders to IgA production may be responsible for the development of this disease.

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Of 608 patients with a diagnois of either gross or microscopic hematuria at their first visit, 280 were found to display abnormalities that could indicate the etiology of the hematuria through examinations, Urologic diseases represented the most frequent etiology (70.5%). Of the 328 patients of unknown etiology, 104 were subjected to long-term follow-up studies. These patients were assessed at an average interval of 37.7 months after their first visit. All patients were living and doing well at the time of questionnaire. Causative diseases were not determined in all but one case. Drug-induced discoloration of the urine was the final diagnosis in this one patient.

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We studied the effects of dilazep dihydrochloride (Dilazep; Kowa), an antiplatelet agent, on rabbit acute serum sickness nephritis induced by intravenous administration of 250 mg/kg of BSA. The dose-dependent influence of this drug was also examined by administration of two different doses of Dilazep, 100 mg/kg/day to 7 rabbits (group A) and 200 mg/kg/day to 4 rabbits (group B), from the 2nd to the 24th day after antigen administration. Dilazep inhibited the release of serotonin from platelets in 4 of the 7 rabbits of group A and in all 4 rabbits of group B. Prevention of immune complex deposition in the glomeruli, of cell proliferation and of the development of proteinuria were also observed in these 8 rabbits, and the effects were more remarkable in the 4 rabbits of group B. Three rabbits of group A, in which Dilazep failed to inhibit serotonin release from the platelets, developed proteinuria. It is considered that Dilazep inhibits serotonin release from the platelets, and thereby inhibits immune complex deposition in the glomeruli, cell proliferation and the development of proteinuria. A dose-dependent influence of Dilazep was finely observed in the effects on the disease. Administration of 100 mg/kg/day of dilazep did not sufficiently inhibit the serotonin release from platelets in 3 out of 7 rabbits, while 200 mg/kg/day of Dilazep inhibited the release of serotonin and the development of glomerulonephritis satisfactorily. Dilazep, as an antiplatelet agent, may represent a useful drug in the treatment of immune complex glomerulonephritis.

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We examined the effects of antiplatelet agents on in vivo platelet function in relation to reduction of proteinuria. Forty-seven patients with glomerulonephritis were studied, of whom 26 were treated with dipyridamole (225-300 mg/day) and 21 were treated with dilazep dihydrochloride (300-450 mg/day, dilazep). Reduction in proteinuria was observed in 8 of the patients treated with dipyridamole (31%), and in 9 of the patients treated with dilazep (43%). In the patients with reduced proteinuria, the concentration of intraplatelet serotonin were increased significantly and the levels of plasma serotonin were decreased significantly by the therapy. The number of patients who became ameliorated in intraplatelet serotonin and plasma serotonin was significantly higher in the patients with reduced proteinuria than in those whose proteinuria unchanged. The plasma β-TG and PF4 levels appeared not to correlate with the reduction in proteinuria. It is concluded that chemical mediators released from platelets, as represented by serotonin, play an important role in the induction of proteinuria. The antiplatelet agents, dipyridamole and dilazep, reduce proteinuria by inhibiting the process involving the release reaction from platelets.

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Using X-irradiation as an inhibitory procedure for macrophage mobilization into glomeruli, the correlation between the rate of appearance of macrophages and the tissue injury expressed in terms of proteinuria was investigated in accelerated Masugi nephritis in the rat. Inhibition of macrophage accumulation in the glomeruli by X-irradiation resulted in significant suppression of the urinary protein excretion at 5 days and 1 week after rabbit nephrotoxic serum (NTS) injection. At 2 weeks, in accordance with an increase in the rate of appearance of macrophages to a level almost equal to the control, the urinary protein excretion increased coincidentally to a level almost equal to the control. Morphological analysis revealed that a subendothelial location and direct contact with the glomerular basement membrane (GBM) by accumulated macrophages was significant in terms of the outcome of proteinuria. The application of non-specific esterase staining for electron microscopy is demonstrated.

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Hemeostatic movements of the enzymatic system in the kidney were analyzed in mice given an aminopeptidase inhibitor, bestatin. In spite of the specific inhibition spectrum of this agent, changes occurred which involved unexpectedly extensive networks of enzymes including exopeptidases, endopeptidases, glycosidases, phosphatase and esterase. By means of multivariate analysis, several principal components were extracted from the movements of the enzyme networks. Time series analysis was performed especially on the first three principal components, since they accounted for almost 80% of the sample variation. Autocorrelation curves of the scores for these three components demonstrated sine curve type oscillations in bestatin treated mice in contrast to atypical ones in control animals. Thus, the seemingly bizarre movements of individual enzymes turned out to be the result of homestatic regulations of enzyme networks in the kidney. This kind of study seems essential for interpreting the chronic movements of enzyme levels in the blood or kidney tissues occurring after administration of physiologically active substances including enzyme inhibitors.

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We investigated the acute effects on the renin-angiotensin system and the pharmacokinetic properties of the angiotensin converting enzyme inhibitor enalapril and its potent active diacid metabolite. Seventeen patients with essential hypertension (EH group) and five hypertensive patients with chronic renal failure (CRF group) were enrolled for this study. In the EH group, the biological half life (t_1/2) of the diacid was 8.4 hours, the maximum serum concentrations (Cmax) and areas under the curve ([AUC]²⁴ ₀) of enalapril and its diacid were 50.6 ng/ml and 32.2 ng/ml, and 171.6 ng h/ml and 413.9 ng⋅h/ml, respectively. In the CRF group, the t_l/2 of the diacid was 10.9 hours, the mean Cmax and [AUC]²⁴ ₀ of enalapril and its diacid were 86.9 ng/ml and 109.8 ng/ml, and 330.0 ng⋅h/ml and 1709.7 ng⋅h/ml, respectively. The renal clearance of total compounds (enalapril + its diacid) in the CRF group (19.6 ml/min) was significantly lower than that in the EH group (110.5 ml/min). A significant positive correlation was found between the inverse of the creatinine clearance (Ccr) and [AUC]²⁴ ₀ (r=0.70, p<0.001; [AUC] ²⁴ ₀ = 10521.6 x 1/Ccr+ 388.1). In conclusion, these results indicate that enalapril may represent a useful antihypertensive agent for the control of blood pressure in patients with chronic renal failure.

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We evaluated the acute response of parathyroid hormone (PTH) and calcitonin (CT) secretion to non-selective and beta-1 selective antagonists and studied the long-term effects of non-selective betaantagonists on calcium metabolism in chronic hemodialysis patients. Administration of exprenolol (non-selective) and metoprolol (beta-1 selective) depressed thePTH secretion similarly. Long-term administration of non-selective beta-antagonists resulted in a significant decrease in PTH, CT and alkaline phosphatase levels without producing any changes in calcium and phosphate levels. These results suggest that 1) beta-1 adrenergic receptors may play an important role in the regulation of PTH secretion, 2) the beta-adrenergic system may also play a role in the regulation of CT secretion, and 3) beta-antagonist therapy may be useful for the prevention of secondary hyperparathyroidism in chronic hemodialysis patients.

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We experienced a case of severe aluminium bone disease complicated by multiple bony fractures involving the ribs and pelvis with a bone biopsy demonstrating marked osteomalacia. Desferrioxamine (DFO) treatment was attempted and various dialysis membranes were tested for aluminium removal. Administration of 4 g DFO during the 1st dialysis in a week (5 hours, three times a week) resulted in a remarkable clinical improvement. The serum aluminium concentration increased to a level 1.5 times the baseline at the end of 2 hours infusion of the first dose of DFO, and reached a peak at the begin-ning of the next dialysis 2 days later. The level of serum aluminium, although decreasing during each dialysis, repeatedly increased again between dialyses over one week until the next dose of DFO. These observations appeared to indicate a continuous increase in serum aluminium over one week follow-ing 4 g infusion of DFO. No differences in aluminium removal by DFO among the three types of dialysis membranes used (couprophane, PMMA, and PAN) were noted.

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The effects of α-human atrial natriuretic polypeptide (α-hANP) on diuresis and natriuresis were studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Intravenous administration of α-hANP caused a marked and dose-dependent increase in urine volume, urinary sodium and potassium excretion. The onset of action was rapid, with the peak effect being observed within 10 min following the a hANP administration in both WKY and SHR. The effect was short-lived (within 10 min) in WKY, whereas it lasted longer than 30 min in SHR. The increase in urine volume was greater in SHR than in WKY at any dosage of ahANP (0.1, 0.5, 1.0 and 5.0 μg/kg). The increase in urinary sodium and potassium excretion also tended to be greater in SHR. These differences in responsiveness suggest that natriuretic factors may play some role in the pathogenesis of hypertension.

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Cortical and papillary micropuncture studies were undertaken to examine the effect(s) of the prostaglandin synthesis inhibitors, meclofenamate and indomethacin, on segmental water transport during hydropenia and volume expansion in the rat. Clearance studies on the intact right kidney revealed no effect of either agent on the glomerular filtration rate, but a significant reduction in water excretion was observed. Water reabsorption in the proximal tubule was unaffected by these agents. An increase in water reabsorption was noted in Henle's loop and in segments between the late distal tubule and base of the papillary collecting duct. The papillary tissue chloride concentration, an index of the papillary tissue tonicity, increased significantly and accounted for the increase in segmental water reabsorption mentioned above. Water reabsorption in the distal tubule, however, was significantly decreased despite a significant reduction in distal tubule fluid osmolality, suggesting that the hydroosmotic permeability in this segment was suppressed. This finding might be accounted for by suppression of the circulating vasopressin level by the prostaglandin synthesis inhibitor. The results suggest that inhibition of prostaglandin synthesis causes antidiuresis not only via the previously reported antagonism of the hydroosmotic effect between prostaglandin and vasopressin but also due to an increased driving force (osmotic gradient) for water reabsorption.

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The urinary N-acetyl-beta-D-glucosaminidase (NAG) and alanine aminopetidase (AAP) activities of patients who received 5-day courses of either dibekacin or cis-platinum were studied. The AAP level revealed a small peak on the 2nd day and a large peak on the 5th day. The NAG values gradually increased with drug administration and decreased after its cessation. Although the patterns were essentially the same with both drugs, cis-platinum caused lesser AAP increases. The difference may be related to the renal handling of the drugs.

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Allopurinol is frequently administered in the presence of advanced renal failure in order to reduce the serum uric acid level. This paper reports a case of aplastic anemia in a hyperuricemie uremic patient caused by allopurinol. The problems of hyperuricemia in renal failure are discussed.

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The present study was undertaken to clarify the clinicopathological features of remitted cases of IgA nephropathy. 27 of 155 patients, who had initial Ccr values of 70 ml/min or more at the time of renal biopsy and were followed up for more than 3 years, had achieved complete remission at the latest observation. Compared with 17 progressive cases who showed the same initial values of Ccr and subsequent renal functional deterioration during similar follow-up periods, the remitted group of 27 patients had a lower grade of urinary protein excretion (p<0.01), milder histological alterations of glomerular and tubulointerstitial sclerosis (p<0.02-p<0.001) and less intense IgA and IgG deposits in the glomeruli (p<0.02, p<0.05) at the initial evaluation, even though the mean known durations of both groups before renal biopsy were quite similar. These results indicate that this type of IgA nephropathy may be considered as a milder form of the disease, suggesting heterogeneity of IgA nephropathy.

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