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The effects of antihypertensive drugs on mesangial cell proliferation were studied in spontaneously hypertensive rats (SHR) with anti-thymocyte serum (ATS) - induced glomerulonephritis. Rats were treated with either enalapril (Group 1), nifedipine (Group 2), or reserpine + hydrochlorothiazide + hydralazine (Group 3), or were untreated (Group 4). The animals were sacrificed 2, 4 and 7 days after ATS injection and the glomerular cell number and degree of mesangial area expansion were examined. A marked, similar decrease in glomerular nuclear cell number (NC) due to severe mesangiolysis was observed in all of the groups on day 2. Thereafter, an increase in NC reflecting mesangial cell proliferation after mesangiolysis occurred in Group 4 on days 4 and 7. In Groups 1 and 2, the NC was significantly smaller than that in Group 4 on days 4 and 7, indicating suppression of mesangial cell proliferation. In Group 3, however, the number of NCs did not differ from that in Group 4 on days 4 and 7, indicating a lack of such suppression by conventional antihypertensive drugs. The degree of mesangial area expansion (MS) showed the same pattern as mesangial cell proliferation. That is, the rapid increases in MS seen in Group 4 on days 4 and 7 were apparently suppressed in Groups 1 and 2, but not in Group 3. Our in vivo observations that both an angiotensin converting enzyme (ACE) inhibitor and a calcium channel blocker suppress mesangial cell proliferation and mesangial area expansion suggest that these agents have practical implications in the treatment of mesangial proliferative glomerular diseases through the suppression of excess mesangial cell proliferation.

The renal hemodynamic response to pressor substances in the diseased kidney has been suggested to be different from that in the normal kidney. The aim of this study was to investigate the effects of endothelin and angiotensin II on renal hemodynamics in experimental nephritis induced by the administration of antithymocyte serum in Wistar rats. This model showed mesangiolytic lesions in the glomeruli on day 2 and hypercellular lesions on day 8. Prior to the injection of either endothelin or angiotensin II, the glomerular filtration rate and renal plasma flow were significantly lower in model rats on day 2 or day 8 than in the control rats. The basal glomerular filtration rate and renal plasma flow on day 8 were negatively correlated with the mesangium cell number. The injection of endothelin (0.5 ng/kg BW) led to a decrease in both renal plasma flow and glomerular filtration rate in rats on day 8 which was significantly greater than that in the control rats. Similarly, angiotensin II infusion (0.2 micrograms/kg BW) reduced both renal plasma flow and glomerular filtration rate in the rats on day 8 and the reductions were significantly greater than those in the control rats. In conclusion, renal hemodynamics in rats with mesangial proliferation of the kidney were more sensitive to both endothelin and angiotensin II than those in the normal kidney.

The accumulation of extracellular matrix (ECM) is an important feature of most forms of progressive glomerular diseases. In order to examine the relationship between ECM synthesis and glomerulosclerosis, we evaluated fibronectin synthesis by glomeruli with the immunoprecipitation of conditioned media from isolated glomeruli in 5/6 nephrectomized spontaneously hypertensive rats (5/6N-SHR). There was no difference in blood pressure between 5/6N-SHR and control SHR throughout the experiment. Two weeks after the nephrectomy, most of the glomeruli were intact and no difference in the synthesis of fibronectin was observed between either groups. Twenty weeks after the nephrectomy, marked glomerulosclerosis associated with an increase in urinary protein was revealed in 5/6N-SHR but no glomerular lesions in control SHR. The synthesis of fibronectin by isolated glomeruli increased in 5/6N-SHR compared to control SHR. The administration of enalapril or hydralazine + reserpine + hydrochlorothiazide markedly attenuated the glomerular sclerosis and urinary protein excretion to a comparable degree, although the later therapy reduced blood pressure more effectively. These antihypertensive therapies also suppressed fibronectin synthesis in the 5/6N-SHR group at week 20. In conclusion, increased synthesis of glomerular fibronectin appeared to contribute to the glomerulosclerosis caused by subtotal nephrectomy and hypertension.

Percutaneous transluminal renal angioplasty was performed in a 63-year-old diabetic woman who had renovascular hypertension with solitary functioning kidney and diffuse atherosclerosis. Angioplasty was technically successful, while thereafter, fever and myalgia of legs occurred with gradual increases in blood urea nitrogen and creatinine. The patient became uremic over a month after angioplasty and was placed on dialysis. She died six months after angioplasty. Autopsy revealed cholesterol embolization in bilateral kidney, pancreas and spleen, causing subacute renal failure. It is suggested that careful assessment of the patient should be made when determining the need for renal angioplasty for renovascular hypertension with a solitary functioning kidney.

Germanium (Ge; atomic number 32, atomic weight 72.6) belongs to IVb group of the Periodic Table and is found as a trace metal in soil, rocks, plants, and animals. It is widely used in industry because of its semiconductive nature. Some biological activities have been shown in Ge derivatives. Recently, patients with persistent renal damage after chronic ingestion of germanium dioxide (GeO2)-containing compounds have been reported in Japan. This study aimed to investigate subacute nephrotoxicity of GeO2 in Lewis male rats. The rats were treated orally with GeO2 for 13 weeks (GeO2 group) and were compared with those treated with GeO2 for only the first 4 weeks (GeO2-4-week group) and with untreated controls. Renal dysfunction was demonstrated by the increased serum creatinine, BUN, and serum phosphate and decreased creatinine clearance. Liver dysfunction was observed as demonstrated by the increased GOT and GPT, and hypoproteinemia by the decreased total protein and albumin in the GeO2 group. However, daily urinary protein excretion or urinalysis did not differ among the groups. Kidney weight and Ge content of tissues were significantly elevated in the GeO2 group. With the light microscope, vacuoles and the depositions of PAS-stained particles, which correspond to electron-microscopic dense granules in the swollen mitochondria, were predominantly observed in distal tubular epithelium in the GeO2 group. Even in the GeO2-4-week group of rats, serum creatinine was increased and the abovementioned histological abnormalities were observed, but were less intense.

Transforming growth factor-β regulates production of proteoglycans by mesangial cells. Accumulation of glomerular extracellular matrix is a prominent feature of most forms of progressive glomerular disease. Since some growth factors may play a role in extracellular matrix production, we examined the effects of transforming growth factor-β (TGF-β), interleukin 1, platelet derived growth factor, and tumor necrosis factor on the production of extracellular matrix components by cultured rat mesangial cells. In control experiments we found that mesangial cells produced two distinct proteoglycans identified as the small chondroitin/dermatan sulfate proteoglycans biglycan (PG I) and decorin (PG II) by showing that their mobility on SDS-PAGE changed upon digestion by chondroitinase ABC, and that they reacted with antibodies raised against synthetic peptides from the core protein sequence of human biglycan and decorin. Exposure to TGF-β for 48 hours stimulated an 8- to 10-fold increase in the biglycan and decorin bands, and induced a structural change detected as a shift in electrophoretic mobility. TGF-β did not demonstrably affect the production of other matrix proteins by the mesangial cells. The other growth factors tested had no comparable effect on the production of proteoglycans or other extracellular matrix components by these cells. Our results show that TGF-β is unique among growth factors in its regulatory effects on mesangial cell proteoglycan production. The release or activation of TGF-β during glomerular injury could mediate the accumulation of proteoglycans in the extracellular matrix and predispose the kidney to development of glomerulosclerosis.

Chronic renal failure developed in 5 patients who were taking germanium dioxide (GeO2)-containing compounds. Renal functional deterioration was slow but progressive and dialysis treatment was necessitated temporarily in 2 patients. After the discontinuation of GeO2, the impaired renal function tended to improve but remained abnormal for an observation period of 10-40 months. The lack of proteinuria and hematuria was characterized as the clinical manifestations. Renal biopsy specimens revealed the tubular epithelial cell degeneration containing hematoxylin-positive fine granules on light microscopy, and electron-dense inclusions in the swollen mitochondria on electron microscopy. These findings localized mainly in distal segment of the tubules. In the rats given GeO2 orally for 10 weeks, similar histological lesions were evident, as manifested by marked weight loss, anemia, azotemia, and negative proteinuria. In the rats given carboxyethylgermanium sesquioxide, these changes were not observed and Ge concentration of kidney was significantly lower than in the rats given GeO2. The present study indicates that chronic GeO2 intake causes progressive renal dysfunction characterized by the degeneration of distal tubules.

P131 Chronic administration of folic acid decreases plasma levels of homocyst(e)ine (Hcy) in hyperhomocyst(e)inemic subjects. Folic acid augments NO release and eliminates superoxide anion production in vitro. In chronic smokers, endothelial function is impaired possibly due to oxidative stress. Accordingly, we examined whether folic acid supplementation improves endothelial function in chronic smokers. We administrated folic acid (20 mg/day, po) or placebo for one week in normohomocyst(e)inemic habitual smokers and age-matched controls and examined flow-mediated vasodilation of the brachial artery by high resolution ultrasonography as a non-invasive measure of endothelial function by a randomized, double- blind, cross-over design. We also measured plasma levels of Hcy, malondialdehyde as an index of oxidative stress, and tetrahydrobiopterin, an essential co-factor of NO synthase and for which synthesis folic acid plays a crucial role, before and after interventions. One week of folic acid supplemetation increased plasma levels of folic acid by 5-fold of the basal level (from 7.2±0.7 to 32.4±2.2 ng/ml, p

68 Insulin resistance syndrome, which constitutes obesity, hypertension, impaired glucose tolerance, and low high density lipoprotein is closely associated with cardiovascular events. Impairment of endothelial function precedes and exacerbates atherosclerosis. Accordingly, the aim of this study was to investigate a possible link among endothelial dysfunction, subclinical atherosclerosis, and insulin resistance syndrome. First, to examine the association between functional changes of large artery and insulin resistance syndrome, flow-mediated vasodilation (FMD) of the brachial artery was examined by high resolution ultrasonography, as a non-invasive measure of endothelial function in subjects without cardiovascular diseases (n=75). Coronary risk factors, including factors constituting insulin resistance syndrome were evaluated as well. Univariate and multivariate analyses revealed that FMD was inversely correlated with body mass index (BMI; r=-.26, p

P130 Iron is a transition metal which generates reactive oxygen species (ROS). ROS-induced oxidative stress impairs endothelial function and plays a central role in the pathogenesis of atherosclerosis. To investigate whether body iron store is associated with endothelial dysfunction via oxidative stress, the effects of 1) parenteral iron loading and 2) iron chelation on endothelial function were measured. 1) In healthy volunteers, we administrated therapeutic dose of iron dextran (0.7 mg/kg body weight, i.v.) or vehicle, and examined flow-mediated vasodilation (FMD) of the brachial artery by high resolution ultrasonography, as a non-invasive measure of endothelial function. We also measured plasma levels of malondialdehyde (MDA), as an index of oxidative stress. Iron loading increased plasma levels of iron (from 89±13 to 232±12 mg/dl, p

Valsalva洞動脈瘤破裂は大動脈基部のValsalva洞が下外方に拡大突出し破綻する比較的稀な疾患である. 我々は本症を合併した慢性腎不全症例を経験した. 患者は44歳男, 昭和55年IgA腎症と診断され, 腎機能が低下傾向にあった. 昭和61年4月突然胸部圧迫感・労作時呼吸困難が出現, 連続性心雑音も認められ, 腎機能も急激に低下したため, 当科に入院した. クレアチニンクリアランスは6-8ml/minと比較的保たれていたが, 腎機能低下による心不全の増悪, ならびに心臓カテーテル検査・大動脈造影・開心術による腎不全の増悪の可能性を考慮し, 早期に血液透析に導入し, 根治術を施行し良好な結果を得た.

To investigate the effect of phosphate binder on adriamycin (ADR)-induced nephropathy, serial changes in renal histology and renal hemodynamics were compared between ADR rats treated with aluminum hydroxide (ADR-AH group) and those without AH (ADR group) for 24 weeks. Urinary protein excretion was less marked in the ADR-AH group than in the ADR group. Serum creatinine in the ADR group increased progressively from week 20, while in the ADR-AH group the increase was less. There were no significant differences in glomerular filtration rate or renal plasma flow between the both groups until week 12 but these parameters decreased to the significantly lower levels at week 24 in the ADR group. Vacuolative degeneration in glomerular epithelium, which was determined as an initial renal lesion, was more marked in the ADR group compared to the ADR-AH group. Glomerular sclerosis and tubulointerstitial changes developed progressively in the ADR group at the later stages. These changes were lessened in the ADR-AH group. In conclusion, AH prevents the progress in ADR-induced nephropathy. The beneficial effects appeared as the preservation of glomerular epithelial cells.

Site of hematoma and clinical outcome in cerebral hemorrhage were analyzed in 25 maintenance hemodialysis (HD) patients and compared with those in 27 non-HD patients. Ganglionic-thalamic hemorrhage wa

We studied the effect of an acute reduction in blood pressure, induced by diltiazem, on the renal hemodynamics of spontaneously hypertensive rats (SHR) with focal glomerular sclerosis, as induced by adriamycin (ADR). Renal plasma flow (RPF) and glomerular filtration rate (GRF) were determined before (first period) and during (second period) intravenous infusion of diltiazem in SHR 4-6 weeks after ADR treatment (group 1), 14-20 weeks after treatment (group 2), and in controls without treatment (group 3). Rats in group 1 had a normal renal function (RPF and GFR) in the first period, which was not significantly different from control rats (group 3). Rats in group 2 showed a reduced renal function, reflected by the lower levels of RPF and GFR, compared with groups 1 and 3. Mean blood pressure decreased equally in the 3 groups by about 50 mm Hg after the infusion of diltiazem. During the second period, 13.4 or 12.4% increase in RPF and a 29.0 or 23.2% elevation of GFR were evident in groups 1 or 3, respectively. In contrast, a 32.0% reduction of RPF was observed in group 2, accompanied by a 25.7% decline of GFR. A reduction in renal function (percent change of RPF or GFR) significantly correlated with the severity of renal dysfunction (RPF or GFR in the first period) in group 2. Thus, the renal function of rats with diseased kidneys is sensitive to an acute reduction in blood pressure by diltiazem, and the sensitivity depends on the degree of renal deterioration.

To investigate the effect of phosphate binders on the progress of renal functional deterioration, aluminium hydroxide (AL) or calcium carbonate (CA) was administered to adriamycin (ADR)-induced progressive renal failure model rats. Urinary protein excretion was reduced in ADR rats treated with AL (ADR-AL group) or CA (ADR-CA group), compared to those without the treatment (ADR group). Urinary phosphate excretion, serum phosphate concentration, and calcium-phosphate product were significantly lower in the ADR-AL and ADR-CA groups than in the ADR group. At week 34, increased serum creatinine, glomerular sclerosis and tubulointerstitial alterations, being marked in the ADR group, were ameliorated in the ADR-AL and ADR-CA groups. However, there was no significant difference in body weight and serum total protein among the three groups. We conclude that AL and CA could both prevent chronic progressive renal deterioration in focal glomerular sclerosis induced by ADR, and preserve the nutritional condition.

Adriamycin-induced nephropathy as a model of chronic progressive glomerular disease. Serial changes in urine protein, blood chemistry, and histology of the kidney were investigated in rats for 28 weeks after injections of adriamycin (ADR). Massive proteinuria, hypoalbuminemia, and hyperlipidemia were observed at week 4 and throughout the experiment. Both BUN and serum creatinine began to increase at week 16 and reached the uremic level at week 28. Light microscopic study of the kidney demonstrated a normal appearance at week 4, vacuole formation in glomerular tuft at weeks 8 and 12, focal and segmental glomerular sclerosis at weeks 16 and 20, and extensive glomerular sclerosis with tubulointerstitial degenerations at weeks 24 and 28. Immunohistologically, IgM with a small amount of IgG and C 3 appeared in the sclerosing glomeruli from week 16. Aggregated human IgG, injected intravenously at week 24, had accumulated mainly in the glomeruli. Electron microscopy revealed degenerative changes of glomerular epithelial cells with small vacuoles in the cytoplasm at week 4. Size of vacuoles increased at the later stage. In conclusion, ADR produced chronic, progressive glomerular changes in rats, which led to terminal renal failure. The segmental glomerular sclerosis and IgM-dominant glomerular deposition in these animals are similar to pathological characteristics of focal and segmental glomerular sclerosis seen clinically.

Pharmacokinetic properties of a new angiotensin-converting enzyme inhibitor, delapril (CV-3317), which converts to two active metabolites (M-1 and M-2) and one inactive metabolite (M-3) after oral administration, were investigated in six subjects with normal, 10 subjects with slight (SRF), and six subjects with markedly (MRF) deteriorated kidney function. The elimination half-life of M-1 was prolonged significantly in subjects with MRF and that of M-3 was also prolonged in subjects with SRF or MRF. The peak plasma drug concentration, time to reach peak concentration (tmax), and AUC were significantly larger in subjects with SRF and MRF than in normal subjects, except for Tmax in subjects with SRF. In M-2 and unchanged delapril, no difference was observed. The 24-hour cumulative urinary excretion of those metabolites was significantly lower in subjects with MRF than in normal subjects. Plasma angiotensin-converting enzyme activity, suppressed at 4 hours in all subjects, remained significantly low in patients with MRF at 24 hours. Blood pressure was reduced more in subjects with chronic renal failure. It was concluded that delapril is excreted mainly through the kidney and its pharmacodynamics and biologic effects are affected by the renal dysfunction. Clinical Pharmacology and Therapeutics (1988) 43, 242–249; doi:10.1038/clpt.1988.27

1. We examined the effects of various levels of dietary protein on the course of adriamycin-induced nephropathy in rats fed with high (30%), intermediately low (10%) or strictly low (5%) protein diets for 24 weeks. 2. In the rats fed on the 30% protein diets, there were massive proteinuria, progressive increases in serum creatinine and focal glomerular sclerosis associated with severe tubulo-interstitial changes. 3. With the 5% dietary protein, proteinuria was decreased, the levels of serum creatinine were preserved within normal ranges and renal histological changes diminished. Weight loss and hypoproteinaemia were more marked. 4. With intermediate protein restriction (10% protein), renal function and plasma protein were preserved but body weight did not increase normally. 5. Aggregated human immunoglobulin G, which had been intravenously injected at weeks 12 and 24, accumulated in the glomeruli more densely in rats fed on the 30% protein diet than in those fed on the 10% or 5% protein diets. 6. We tentatively conclude that functional and histological deterioration of focal glomerular sclerosis can be prevented by appropriate restriction of dietary protein; however, severe protein restriction does aggravate nutritional states.

AGEs activate mesangial TGF-β–Smad signaling via an angiotensin II type I receptor interaction. Background The renin-angiotensin system (RAS) and the accumulation of advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetic nephropathy. Whether there is a functional interaction between the RAS and AGEs in diabetic nephropathy is not known. In this study, we investigated whether AGEs could activate autocrine angiotensin II (Ang II) signaling and subsequently induce transforming growth factor-β (TGF-β)–Smad signaling in cultured rat mesangial cells. Methods The intracellular formation of reactive oxygen species (ROS) was detected using the fluorescent probe CM-H 2 DCFDA. Ang II was measured by radioimmunoassay. TGF-β released into media was quantitatively analyzed in an enzyme-linked immunosorbent assay (ELISA). Smad2, p27 Kip1 (p27), fibronectin, and receptor for AGEs (RAGE) protein expression were determined by Western blot analysis. TGF-β–inducible promoter activity was analyzed by a luciferase assay. DNA synthesis was evaluated by 5-bomo-2′-deoxyuridine (BrdU) incorporation and de novo protein synthesis was determined by [ 3 H]leucine incorporation. Results AGEs increased intracellular ROS generation in mesangial cells, and this effect was significantly inhibited by an antiserum against RAGE. AGEs also were found to stimulate Ang II production in a time- and dose-dependent manner, which was completely prevented by an antioxidant, N -acetylcysteine (NAC). AGE-induced TGF-β overproduction was completely blocked by candesartan, an Ang II type 1 receptor (AT 1 R) antagonist. Both candesartan and neutralizing antibody against TGF-β completely prevented AGEs-induced Smad2 phosphorylation and TGF-β–inducible promoter activity. Furthermore, AGEs were found to inhibit DNA synthesis and to stimulate de novo protein synthesis and fibronectin production in association with up-regulation of p27. All of these phenomena were completely prevented by candesartan or a polyclonal antibody against TGF-β. Conclusion The present study suggests that AGE-RAGE–mediated ROS generation activates TGF-β–Smad signaling and subsequently induces mesangial cell hypertrophy and fibronectin synthesis by autocrine production of Ang II. This pathway may provide an important link between metabolic and haemodynamic factors in promoting the development and progression of diabetic nephropathy.

Ischemia/reperfusion injury is the leading cause of acute tubular necrosis. Nitric oxide has a protective role against ischemia/reperfusion injury; however, the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in ischemia/reperfusion injury remains unclear. ADMA is produced by protein arginine methyltransferase (PRMT) and is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). Here we examined the kinetics of ADMA and PRMT and DDAH expression in the kidneys of ischemia/reperfusion-injured mice. After the injury, DDAH-1 levels were decreased and renal and plasma ADMA values were increased in association with renal dysfunction. Renal ADMA was correlated with 8-hydroxy-2′-deoxyguanosine, a marker of oxidative stress. An antioxidant, N-acetylcysteine, or a proteasomal inhibitor, MG-132, restored these alterations. Infusion of subpressor dose of ADMA exacerbated renal dysfunction, capillary loss, and tubular necrosis in the kidneys of ischemia/reperfusion-injured wild mice, while damage was attenuated in DDAH transgenic mice. Thus, ischemia/reperfusion injury–induced oxidative stress may reduce DDAH expression and cause ADMA accumulation, which may contribute to capillary loss and tubular necrosis in the kidney.

Risk factors for renal glomerular and vascular changes in an autopsy-based population survey: The Hisayama Study. Background Information of the effect of cardiovascular risk factors on renal glomerular and vascular changes is scarce in the general population. Method Between 1962 and 1994, 1394 autopsies were performed in Hisayama, for a total autopsy rate of 80%. Of these, 839 individuals who preserved adequate renal tissues and had recent health examinations data before death were eligible for the present study. We examined the degree of glomerular sclerosis, renal arteriolar hyalinosis, and arteriosclerosis, and evaluated their risk factors by means of a logistic regression model. Results The development of glomerular sclerosis, arteriolar hyalinosis, and arteriosclerosis were 16%, 16%, and 18% in men, respectively, and 27%, 15%, and 24% in women, respectively. All these frequencies increased linearly with advancing age. In the multivariate analysis, both age and systolic blood pressure were significant independent risk factors for almost all these glomerular and vascular changes. In addition, glucose intolerance and proteinuria for men were found to be significant risk factors for glomerular sclerosis. Elevated total cholesterol levels significantly increased the risk of arteriolar hyalinosis in men. Electrocardiogram (ECG) abnormalities were an independent risk factor for arteriosclerosis in both men and women, and proteinuria was an additional risk factor in women. Alcohol intake tended to have a protective effect on glomerular sclerosis and arteriosclerosis in women. Conclusion Our data confirmed that age and systolic blood pressure are common risk factors for all glomerular and renal vascular changes in the general population. In addition, glucose intolerance, total cholesterol, ECG abnormalities, and proteinuria affect either glomerular or vascular changes.

In order to investigate the influence of diabetes mellitus on immune complex-mediated nephritis , we produced Heymann nephritis in streptozotocin-induced diabetic rats (DM-HN group) in which the clinical course for 24 weeks and histological changes were examined. Nondiabetic rats with Heymann nephritis (HN group) and diabetic rats (DM group) were also examined as controls. The degree of proteinuria, hypoproteinemia, hyperlipidemia and anemia were more pronounced and the mortality rate was higher in the DM-HN group than in the HN group or in the DM group. Histologically, larger and more subepithelial or intramembranous electron-dense deposits as well as a more markedly thickened glomerular basement membrane (GBM) were observed in the DM-HN group than in the HN group. In conclusion, the nephrotic manifestations and histological changes in the GBM in Heymann nephritis were augmented by the association with diabetes mellitus.

1. To investigate the influence of age on the remnant kidney, unilateral nephrectomy was performed in rats at 1 day (group N-0), 2 weeks (group N-2), 4 weeks (group N-4) or 8 weeks (group N-8) of age. Serial changes in urinary protein during 48 weeks after the uninephrectomy and blood chemistries and renal histology at week 48 were compared between the groups. 2. The increase in proteinuria was significantly greater in groups N-0, N-2 and N-4 than in group N-8 from week 32 to week 48 after the uninephrectomy. There was no significant difference in urinary protein between groups N-0, N-2 and N-4. Hypoproteinaemia and hypoalbuminaemia were also more severe in groups N-0, N-2 and N-4 than in group N-8 at week 48. 3. A compensatory renal growth in groups N-0 and N-4 was significantly greater than that in group N-8 at week 48 after the uninephrectomy. 4. Focal and segmental glomerular sclerosis, a characteristic finding in the uninephrectomy groups, was significantly more marked in groups N-0, N-2 and N-4 than in group N-8 at week 48. 5. We conclude that uninephrectomy at young ages leads to increased incidence of glomerular sclerosis in rats compared with uninephrectomy in the adult.

Suppression of various types of immune reactions including antibody (Ab) production, cell-mediated cytolysis (CMC), and delayed footpad reaction (DFR) was compared in EL-4 lymphoma-bearing syngeneic mice. In the primary response, the suppression of Ab production and CMC was detected 4 days after tumor inoculation, reached a peak on day 8, and then disappeared. The suppression of DFR was detected on day 1 and persisted to day 12. The suppressive effects of tumor-bearing mice could be transferred with sera to normal recipients, and the degree of the suppressive effect in tumor-bearing hosts correlated with the suppressive effect of sera but not with tumor size. In the secondary response, the suppressive effect of the tumor-bearing state was detected only on DFR. Spleen cells of these hosts were able to transfer positive DFR adoptively to normal recipients, indicating the presence of sensitized lymphocytes in the absence of expression. DFR of normal mice in the primary response was suppressed by transfer of sera of tumor-bearing mice befor elicitation, at which time sensitized lymphocytes should already have been raised. The very high susceptibility of DFR to the suppressive effects of the tumor-bearing state may be ascribed to the distinct susceptibility of mononuclear cells, probably of the macrophage series, which are required as secondary cells for expression of DFR. Further studies with Sephadex G-200 fractionation of the sera from the tumor-bearing mice showed that the immunosuppressive activity appeared in the initial fraction containing relatively high-molecular-weight materials.

1. Effect of hypertension on progressive renal disease was examined in spontaneously hypertensive rats (SHR) with experimental focal glomerular sclerosis, produced by the intravenous administration of adriamycin (ADR). Serial changes of urinary protein, blood pressure and blood chemistry for 22 weeks after ADR-treatment, and renal histology at week 22, were compared between ADR-treated SHR (group ADR-HT) and ADR-treated SHR given antihypertensive drugs (group ADR-AH). 2. Hypertension persisted in group ADR-HT, while blood pressure markedly decreased in group ADR-AH, after oral administration of antihypertensive drugs (guanethidine and hydralazine). 3. Massive proteinuria, hypoalbuminaemia and hypercholesterolaemia were observed throughout the experiment both in group ADR-HT and in group ADR-AH. Urinary protein levels were significantly larger in the former at weeks 12 and 16. 4. Blood urea nitrogen and serum creatinine levels increased progressively from week 16 in the ADR-treated rats. The increase was more rapid in group ADR-HT than in group ADR-AH. In group ADR-HT, 10 of 25 rats died between weeks 20 and 22, whereas all in group ADR-AH survived. 5. Histologically, ADR-treated rats showed focal glomerular sclerosis with tubulointerstitial changes. The lesions were more extensive in group ADR-HT than in group ADR-AH. 6. We conclude that hypertension influences the progress and prognosis of chronic progressive renal disease, as induced by adriamycin.

Primary in vivo production of antibody to sheep red blood cells (SRBC) was consistently suppressed in EL 4 tumor-bearing C57BL/6 mice, but the secondary response was not suppressed. This suppressed primary in vivo production of antibody was partially restored by systemic administration of Corynebacterium parvum. For investigation of the mechanism of the immunosuppression in tumor-bearing mice and the effects of C. parvum, the accessory cell function of adherent cells from tumor-bearing mice and C. parvum-treated tumor-bearing mice in in vitro cultures was studied. Peritoneal and splenic cells from tumor-bearing mice were less efficient in promoting in vitro production of antibody to SRBC by macrophage-depleted normal nonadherent cells than the adherent cells from normal mice. C. parvum treatment restored the accessory cell function of splenic adherent cells from tumor-bearing mice but not that of peritoneal cells. Furthermore, adherent cells from tumor-bearing mice did not show suppressive activity against the in vitro plaque-forming cell response.

To investigate the effect of phosphate binding on the progress of chronic renal disease, aluminium hydroxide was administered to rats with focal glomerular sclerosis experimentally induced by adriamycin over a period of 28 weeks (group ADR-AH). The clinical data were examined every 4 weeks and the renal histology at week 28 were compared to those in adriamycin-injected rats without aluminium hydroxide treatment (group ADR). Urinary protein excretion was less marked in group ADR-AH than in group ADR at weeks 8 and 12. Serum creatinine in group ADR started to increase at week 20 and continued to rise until week 28, while in group ADR-AH it increased less, the difference being significant. Serum phosphate was lower in group ADR-AH than in group ADR at weeks 8, 12, 24, and 28. Focal glomerular sclerosis and tubulointerstitial changes were observed in both adriamycin-injected groups regardless of aluminium hydroxide treatment at week 28, although these changes were much less severe in group ADR-AH. There were no differences in body weight and serum albumin between the two groups. We conclude that aluminium hydroxide could prevent the renal deterioration in focal glomerular sclerosis induced by adriamycin without affecting the nutritional state.

The effects of nephron loss on the clinical and histological picture of experimental membranous nephropathy were examined for 18 weeks in five-sixths nephrectomized rats with Heymann nephritis (HN-5/6N group). Heymann nephritis-induced rats without nephrectomy (HN group), normal rats with 5/6 nephrectomy (5/6N group) and normal rats without nephrectomy (control group) were also examined for comparison. A rapidly progressive increase in urinary protein, BUN and serum creatinine was observed after renal ablation in the HN-5/6N group. Light microscopic study revealed global or segmental sclerosis in most of the glomeruli, crescent formation in some of the glomeruli and marked tubulointerstitial changes. Electron microscopic study demonstrated vacuolation and necrosis of podocytes, detachment of podocytes from the glomerular basement membrane (GBM) and fibrin exudation into Bowman's space. Proteinuria was also marked but renal function was not impaired in the HN group. In the 5/6N group, proteinuria was mild and elevation in BUN and serum creatinine was apparent but not progressive. There were no differences in the depositions of IgG, C3 and electron-dense materials on GBM between the HN-5/6N group and the HN group. In conclusion, renal mass reduction associated with high flow and pressure to the remnant glomeruli could lead to extensive glomerular sclerosis and to a deterioration in renal function, in the case of pre-existing nephritic lesions.

The effect of dietary protein restriction on the progress of renal dysfunction was investigated in rats with adriamycin (ADR)-induced progressive glomerular disease. Dietary protein was reduced from 20% (normal diet) to 5% (low protein) immediately after (ADR-0w), 8 weeks (ADR-8w) or 16 weeks (ADR-16w) after the repeated injection of ADR. In the unrestricted (ADR-UR) group rats were fed 20% of protein throughout the 24-week experiment. Massive urinary protein developed immediately after ADR injection and significantly decreased by reducing dietary protein in all the groups (ADR-0w, ADR-8w, ADR-16w). However, plasma protein and serum albumin were low irrespective of the improvement of urinary protein. BUN and serum creatinine were unchanged in ADR-0w and ADR-8w groups, while they were increased in ADR-16w and ADR-UR groups. Glomerular sclerosis and tubular atrophy were much less severe in ADR-0w and ADR-8w than in ADR-16w and ADR-UR groups. The results indicate that dietary protein restriction checks the further progress of renal dysfunction. The importance of the time when protein intake should be reduced is discussed.

To examine the effect of age on a compensatory renal growth, adaptive renal hemodynamics and renal histology in solitary kidney, unilateral nephrectomy was performed in young rats at 4 weeks of age (group 4-UN) or in adult rats at 10 weeks of age (group 10-UN). Urinary protein was measured every 4 weeks until the 48th week. Serial changes in kidney weight, glomerular filtration rate (GFR), renal plasma flow (RPF) and renal histology were investigated at weeks 4, 8, 24 and 48 after the uninephrectomy. Increase in proteinuria was significantly greater in group 4-Un than in group 10-UN from weeks 32-48 after uninephrectomy. The remnant kidney showed a compensatory enlargement which was more marked in group 4-UN than in group 10-UN at weeks 24 and 48. GFR or RPF in group 4-UN was significantly greater than that in group 10-UN at weeks 4, 8, and 24. Focal and segmental glomerular sclerosis was evident at week 24 or later in the uninephrectomized rats, being more severe in group 4-UN than in group 10-UN at week 48. We conclude that uninephrectomy in young rats leads to augmented compensatory renal growth and glomerular hyperperfusion, resulting in extensive glomerular sclerosis compared to that in adult rats.