The renal collecting tubules are responsible for secretion of K⁺ into the urine and play a major regulatory role in K⁺ homeostasis of mammals. There are several factors which affect K⁺ secretion, including aldosterone, K intakes and acid-base balance. We have cloned a complementary DNA encoding a K⁺ channel of the rabbit renal cortical collecting tubule cells (RACTKI). RACTKI is a voltage-independent, pH sensitive K⁺-permeable channel, encoding 284 amino-acids, and putatively having two transmembrane segments. This channel is located not only in the luminal membrane of the collecting duct but also in the vascular smooth muscles of the several arteries. The expression of RACTKI is regulated by external pH but neither by aldosterone nor by K⁺ concentration in cultured cells. Thus RACTKI seems to be a unique and distinct from K⁺ channels in that it is regulated specifically by changes in ambient pH, contributing to the pH dependent urinary K⁺ excretion.

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Contraction of the pre- and postglomerular arteries plays an important role in the regulation of glomerular blood flow. Mesangial cells may also be involved in the mechanism of this regulation, but it has not been clarified yet whether or not mesangial cells and vascular smooth muscles show an identical phenotype, especially in terms of their contractile proteins. In this study, in order to elucidate any difference in the cellular phenotypes between mesangial cells and renal vascular smooth muscles, we investigated the localization of myosin heavy chain isoforms using a monoclonal antibody against SM1 and SM2. Both SM1 and SM2 are specific to smooth muscles. SM1 is specifically expressed in smooth muscles from early development and SM2 appears after birth. In normal renal tissues, SM1 and SM2 were expressed only in the smooth muscle cells of the arterioles and small arteries. However, glomerular cells, including mesangial cells, were not stained with either anti-SM1 antibody or anti-SM2 antibody. Localization of SM1 and SM-2 was similar to that of α-smooth muscle actin (SM α-actin). Staining for SM-1 was not observed in the mesangial areas of renal tissues with glomerular disease. These results clearly indicate that mesangial cells have a different phenotype from that of vascular smooth muscle cells in terms of their contractile proteins.

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We have reported previously that loop diuretics, especially azosemide and ethacrynic acid, may act not only on the AVP receptor site, but also on the post-AVP receptor site in rat renal tubular basolateral membranes. The purpose of this study was to examine whether loop diuretics (furosemide, azosemide, ethacrynic acid) affect the post-AVP receptor components, using GTP-γS, forskolin and cholera toxin as tools acting distal to the receptor. Adenylate cyclase activity stimulated by 10^-9 M AVP was inhibited more potently by azosemide and ethacrynic acid than by furosemide at the concentration of 10^-3 M . Azosemide and ethacrynic acid at concentrations above 10^-4 M also significantly decreased the enzyme activity that was stimulated by 10^-7 M GTP-γS and 10^-5 M forskolin, while significant inhibition by furosemide was observed only at 10^-3 M. In addition, the inhibitory effect of these loop diuretics on cholera toxin-stimulated enzyme activity was almost similar to the results observed in AVP-, GTP-γS- or forskolin-stimulated the enzyme activity. From these results, we conclude that loop diuretics, especially azosemide and ethacrynic acid, directly affect adenylate cyclase in part as well as the AVP receptor site.

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This paper retrospectively examines the association of outcome with histological and clinical manifestations in 107 pediatric patients with idiopathic nephrotic syndrome (INS) . At the time of renal biopsy, the patients were between 2 and 15 years of age. The interval from the onset of the disease to renal biopsy ranged from 1 to 156 months with a mean of 21 months. Continuous clinical follow-up was successfully conducted in 96 patients. The average duration of INS in these patients was 86.6 months (31 to 208 months). IgM deposition in the mesangium may play an important role in the pathogenesis of INS and our data showed that even in a minor glomerular abnormality (MCNS) subgroup, nearly half of the cases (42.9% ) showed mesangial IgM deposition. However, the severity of hematuria, response to drug therapy with either steroids or cyclophosphamide, and the outcome, were not related to the presence or absence of IgM deposition, but were more closely associated with the type of histological category. The subgroup of patients with focal segmental glomerulosclerosis (FSGS) and diffuse mesangial proliferation (FSGS + DP) showed the most significant ultrastructural changes with positive mesangial IgM deposition (73.6%). The presence of IgM deposition in most of the patients in the subgroups with diffuse mesangial proliferative glomerulonephritis (DPGN) and FSGS + DP closely corresponded to the presence of electron-dense mesangial deposition. The FSGS + DP subgroup had a high incidence of denudation, vacuolization and detachment of podocytes, partial collapse of the glomerular basement membrane, and a very high incidence of resistance to steroid therapy . In patients with infrequent relapse, the addition of cyclophosphamide to steroid therapy was helpful in achieving long-term remission. There were 4 cases of mortality, of which 1 was an infrequent relapser. In addition, 6 cases showed impairment of renal function, of which 3 had marked deterioration in renal function to the end-stage. Seven patients showed growth retardation, of whom 3 were infrequent relapsers. These results indicate that clinical manifestation and outcome are not related to the presence or absence of mesangial IgM deposition, but depend on the type of histological category . The results of EM and IF studies suggest that alteration in the capillary wall may serve as an important risk factor for mesangial proliferation and focal sclerosis rather than pathogenic mesangial change itself . Early introduction of cyclophosphamide therapy or other suitable medication in addition to conventional steroid treatment is necessary to avoid deterioration in renal function and growth retardation, even in cases of infrequent relapse .

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From 1981 to 1987, renal specimens obtained from 91 children with idiopathic nephrotic syndrome were categorized into 5 histologic subgroups, according to the WHO classification. We analyzed differences in the ratios of the size of the mesangial stalks and attached capillary, including the Bowman′s space between the capillary tufts (E), mesangial matrix (MX), and approximate capillary lumens (E-Mx) to the whole glomerular area of these subgroups using the histomorphometer-IBAS. Focal segmental glomerulosclerosis with diffuse mesangial proliferation (FSGS + DP) had the largest matrix area (MX/ G>0.5), and smallest capillary lumen size (E/G-MX/G) (0.3474±0.0702). On the contrary, FSGS with minimal change (FSGS + MC) had the smallest mesangial matrix (MX/G), 0.2834±0.07726, but preserved a larger capillary lumen (0.427±0.1215). The approximate size of capillary lumens, from the smallest to the largest, was in the following order: FSGS + DP, diffuse mesangial proliferative glomerulonephritis (DPGN), focal segmental proliferative glomerulonephritis (FSPGN), FSGS + MC and minimal change nephrotic syndrome (MCNS). The ratio of the total number of mesangial cells to the area of the whole glomerulus (MCN/G) derived from the light microscopic examination was parallel to the value of Mx/G obtained by the histomorphometric technique. In summary, we introduced the histomorphometric technique using the histomorphometer-IBAS for quantitative measurement of various areas in the glomeruli. The data derived from the system is compatible with those obtained by experienced nephrologists, suggesting that the histomorphometric technique is helpful in histopathology. It is hoped that this new methodology will be used more extensively in the near future.

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To determine the clinical characteristics and long-term prognosis of 11 Japanese systemic lupus erythematosus (SLE) patients who were starting dialysis, we studied the clinicopathological findings before dialysis and during the clinical course after dialysis. Patients were divided into three groups: Group A consisting of temporary dialysis patients (n = 5); Group B consisting of early-death patient (n =1); and Group C consisting of maintenance dialysis patients (n = 6). At the start of dialysis, the progression pattern of renal failure in all Group A patients was either acute exacerbation of chronic renal failure (CRF) or rapidly progressive glomerulonephritis (RPGN). The pattern in Group C was mostly CRF (83%). Three patients from Group A and three from Group C were still alive at the latest follow-up (mean follow-up period was 11.0 years, ranging from 1.8 to 16.2 years) and they showed no signs of clinical or serological activity. Infection was the cause of death in 3 of the 5 patients who died. We suggest that dialysis can be discontinued in patients with SLE who receive dialysis for acute exacerbation of CRF or RPGN. After the initiation of dialysis, patients tend to show diminished SLE activity, infection is the major contributor to the poor prognosis of SLE patients receiving dialysis.

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To evaluate the role of histones and ubiquitin in lupus nephritis, we searched for glomerular deposits of histones and ubiquitin in renal biopsy specimens from 53 patients with systemic lupus erythematosus (SLE) and 30 with non-lupus glomerulonephritis. Glomerular immunofluorescence staining revealed positive for histone H2A, H1 + H3, H4 and ubiquitin in 49.1% (26/53), 45.3% (24/53), 32.1% (17/53) and 22.6% (12/53) of the SLE patients, respectively. Non-SLE renal biopsies revealed absence of positive staining with histone H2A, H1 + H3, H4 and ubiquitin. The positive incidence of histone H1 + H3 and ubiquitin in diffuse proliferative lupus nephritis was significantly different (p<0.01) from that in minor glomerular abnormality. Levels of CH50 in patients with glomerular deposition of histone H1+H3 (p < 0.001) and ubiquitin (p < 0.01) were significantly lower than in patients without deposition. Levels of anti-DNA antibody in patients with glomerular deposition of histone H1 + H3 were significantly higher than in patients without deposition (p < 0.05). Only the positive incidence of glomerular deposition of ubiquitin was correlated with the histological activity index (p <0.05). These results suggest that histones and ubiquitin may play an important role in the induction of lupus nephritis.

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Hyperphosphatemia is one of the major problems requiring management in the majority of hemodialysis patients and they require phosphate-binding agents to control the hyperphosphatemia. Aluminum hydroxide and calcium compounds are used currently as phosphate-binding agents to treat hyperphosphatemia, but these compounds can cause undesirable side effects. Therefore, the develop-ment of new phosphate-binding agents is imperative. It is well known that oral and intravenous administration of iron causes hypophosphatemia. We hypothesized that this side effect of iron may be beneficial for the treatment of hyperphosphatemia in hemodialysis patients. Consequently, we conducted a fundamental and clinical investigation of the effects of iron administration. Membrane permeability of phosphorus in a mixture of sodium ferrous citrate and dessicated aluminium hydroxide in the presence of hydrogenated lecithin as a phosporic compound was examined. Fifteen patients undergoing hemodialysis were treated with 150 mg of sodium ferrous citrate given orally for eight weeks. The permeability of the filtering membrane to phosphorus decreased in accordance with the dosage of sodium ferrous citrate and dessicated aluminum hydroxide. The degree of phosphate-binding effect of sodium ferrous citrate was larger than that of dessicated aluminum hydroxide. Serum phosphorus decreased significantly during the experiment. These results suggest that the oral administration of sodium ferrous citrate as a new phosphate binder is a useful therapeutic method for hemodialysis in patients with hyperphosphatemia.

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Various types of glomerulonephropathy have been reported in patients with malignant lymphoma. The present report describes a 21-year-old man with non-Hodgkin's lymphoma who developed renal insufficiency 4 months after undergoing autologous bone marrow transplantation without combined total body irradiation treatment. At the presentation of renal dysfunction, the malignant lymphoma had been in complete remission. A renal biopsy specimen revealed glomerular changes resembling those seen in patients with hemolytic uremic syndrome. However, hematologic examinations exhibited no evidence of thrombocytopenia or thrombotic microangiopathy, such as red cell fragmentations on the peripheral blood smear. Although the etiology of this nephropathy remains unclear, the chemotherapeutic agents administered in conditioning regimens for bone marrow transplantation were suspected of contributing to the renal insufficiency. Methylprednisolone pulse therapy appeared to be effective in arresting progression of the nephropathy. This case indicates that renal function should be monitored carefully in patients with malignant lymphoma after bone marrow transplantation, even if such patients lack the signs or symptoms of thrombotic microangiopathy.

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