In the past year, major advances have been made in understanding the role of cytokines in the pathogenesis and progression of chronic glomerulonephritis. This paper reviews recent data on the pivotal roles of cytokines including interleukins-1 and-6, tumor necrosis factor, platelet-derived growth factor, transforming growth factor-β, fibroblast growth factor and insulinlike growth factor in mediating glomerular cell proliferation and in leading to glomerulosclerosis

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To elucidate the effects of recombinant human erythropoietin (rUuEPO) on endothelial cell proliferation, protein synthesis and endothelin-1 (ET) production by endothelial cells were examined in a cultured endothelial cell (EC) system. EC, incubated with various concentrations of rHuEPO (0, 1000, 5000, 10000mU/ml) for up to 3 days exhibited dose-dependent cellular proliferation that could be inhibited by anti-rHuEPO rabbit antiserum. DNA and protein synthesis, measured by the uptake of ³H-thymidine and ³H-leucine, respectively, showed dose-dependent increases after incubation of confluent EC in the resting phase of the cell cycle with various concentrations of rHuEPO (0, 1000, 2500, 5000, 10000mU/ml) for 18 h. After an additional 6-h culture with rHuEPO at 5000mU/ml or more, the supernatant concentrations of immunoreactive ET showed significantly greater values than those without rHuEPO. Furthermore, rHuEPO increased the DNA synthesis by EC, which had been cultured in E-BM medium containing 0.5%or 2% FBS for 3 h, and which were recultured in E-BM medium containing 5% FBS or containing 2% FBS with 10 ng/ml EGF for 15 h. These results suggest that rHuEPO directly stimulates EC proliferation as a competence factor, and also accelerates endothelin-1 production in association with stimulation of DNA and protein synthesis by EC.

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To determine the role of endothelium-derived nitric oxide (EDNO) in mediating the natriuretic response to acute extracellular volume expansion (ECVE) with isotonic saline (3% of body weight per hour), the diuretic and natriuretic responses to ECVE were studied in anesthetized Sprague-Dawley rats during the intravenous infusion of an EDNO synthesis inhibitor, NW-nitro-L-arginine methyl ester (L-NAME). Intravenous infusion of L-NAME at the dose of 5μg/kg/min significantly inhibited the diuresis and natriuresis in response to ECVE by 58% and 67%, without altering arterial pressure, effective renal plasma flow, glomerular filtration rate and basal excretory function. This inhibitory effect of L-NAME on the diuretic and natriuretic responses to ECVE was attenuated by the infusion of the EDNO synthesis precursor, L-arginine (lmg/kg/min), but not by D-arginine. In addition, pretreatment with 0.3mg/kg of the angiotensin II receptor antagonist, L-158, 809, normalized the diuretic and natriuretic responses to ECVE in L-NAME-treated rats, suggesting an angiotens-in-II-dependency of the reduced renal excretory response to ECVE during EDNO synthesis inhibition. Neither L-arginine nor L-158, 809 alone significantly altered the renal excretory response to ECVE compared with vehicle-treated control rats. These results suggest that EDNO might play an important role in the regulation of sodium and water excretion during ECVE, and indicate a possible interaction between EDNO and angiotensin II on the renal excretory function.

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Renal hemodynamic responses were studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto Rats (WKY) to two acute stresses: environmental stress (foot shock (FS) and air jet (AS)). The effects of calcium channel blocker (benidipine) and al blocker (urapidil) on these responses were studied using an ultrasonic pulsed Doppler flowmeter. The increments in mean arterial pressure (MAP) and renal vascular resistance (RVR) were greater in SHR during both stresses. On the other hand, the decrease in the renal blood flow (RBF) with these stresses almost disappeared with renal denervation. These renal hemodynamic responses in SHR disappeared with α1 blocker (urapidil), but not with calcium channel blocker (benidipine). The sympathetic nervous system became hyperactive in SHR under environmental stress, Which induced specific renal hemodynamic change. These results suggest that investigations on essential hypertension should focus on clarifying not only systemic hypertensive reaction, but also changes in renal hemodynamics. Furthermore, it is necessary for antihypertensive therapy to take these hemodynamic changes into considera tion.

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The importance of the distribution of intrarenal blood flow in the regulation of various renal functions, such as urine concentration and sodium excretion, has been well recognized. However, there have been no reliable methods to measure local flow in the kidney in vivo. The present study demonstrated the usefulness of contrast ultrasonography combined with injection of sonicated 5% albumin for assessment of the distribution of renal cortical blood flow in eleven mongrel dogs. The left kidney was displayed by tomographic echography, and microbubbles of sonicated albumin were injected into the abdominal aorta above the left renal artery. Video density time curves were generated and fitted to a time-intensity curve. Intrarenal infusion of acetylcholine (4.0 t g/kg/min) increased renal blood flow (RBF) from 2.5±0.3 to 4.6±1.0 ml/min/g kwt (p<0.01), and norepinephrine (0.5, tg/kg/min) decreased RBF from 2.5±0.3 to 1.2±0.5 ml/min/g kwt (p<0.01). There were significant positive correlations between percent change in RBF and peak intensity and area under the curve, which were calculated with a time-intensity curve. Furthermore, the inner/outer renal cortex ratio of peak intensity significantly increased during acetylcholine infusion (0.72±0.11 vs 0.86±0.09; p<0.01), whereas no significant change was observed during norepinephrine infusion. These results suggest that renal contrast ultrasonography may be useful for real-time assessment of the distribution of renal cortical blood flow in vivo.

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The indication of low salt diet for the management of hypertension associated with pregnancy is controversial. We studied the effect of a low-salt diet (less than 5g/day) on pregnancy-induced hypertension compared to patients with hypertension due to chronic renal failure and essential hypertension. In chronic renal failure, mean blood pressure decreased from 115.3±3.0mmHg to 92.1±2.6mmHg (p<0.001) and in essential hypertension, from 117.7±3.1mmHg to 108.5±3.5mmHg (p<0.01). However, in pregnancy-induced hypertension, the blood pressure did not change significantly. CUA/Ccr ratio, the indicator of plasma volume, decreased significantly from 8.7±1.5% to 3.8±0.7% (p<0.001) after salt restriction. CUA and mean blood pressure in patients with preeclampsia were negatively correlated significantly (r=-0.51, p<0.05). There was a significant correlation between CUA and urinary sodium excretion (r=0.67, p<0.001). These results indicate that a low-salt diet is not only ineffective, but also accelerates volume depletion in preeclampsia.

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Two patients with minimal amyloid deposition in association with nephrotic syndrome are reported. Since the amyloid deposits in each renal biopsy specimen were inconspicuous, both were first thought to be minimal glomerular changes. A few widely scattered, silver-positive, epimembranous spicules were found on careful reexamination by light microscopy. Congo red stain and electron microscopy confirmed the presence of small glomerular amyloid deposits and amyloid fibrils. Furthermore, immuno-fluorescence microscopy showed partial IgA deposits in the mesangial area and capillary wall. We therefore urge careful examination to detect amyloid deposits of all kidney Biopsy specimens of minor glomerular abnormalities, or glomerulonephritis with IgA deposits from elderly patients with nephrotic syndrome. Light microscopy of Congo-red-stained sections and electron microscopy of the fibrillar structure very useful for the detection of small amyloid deposits.

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The incidence of renal parenchymal hypertension is highest in patients with secondary hypertension. It is important to prevent the progression of renal dysfunction by appropriate treatment, especially by means of antihypertensive drugs. Calcium channel blockers are considered to have the advantage as antihypertensive drugs of maintaining the renal blood flow, even though the perfusion pressure may be decreased. However, these drugs can involve the risk of deteriorating the glomerular function due to hyperfiltration. To investigate whether calcium channel blockers can prevent the deterioration of renal function in renal parenchymal hypertensive patients, we administered manidipine hydrochloride (20 mg, once a day, 24 weeks ) to 16 outpatients and evaluated its effects on blood pressure and renal function. The following results were obtained. (1) The systolic and diastolic pressure decreased from 2 and 4 weeks after administration, respectively. A stable antihypertensive effect appeared thereafter and no change was observed in the pulse rate. (2) The renal vascular resistance tended to decrease slightly. The glomerular filtration rate and renal blood flow did not change in spite of the decreased perfusion pressure. (3) No changes were seen in urinary protein, endocrine factors and cardiac function. (4) In some of the cases with decreased GFR (<70ml/min), the drug could not prevent deterioration of the renal function and did not produce an antihypertensive effect.

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We evaluated saliva concentration as a parameter of therapeutic drug monitoring (TDM) of Ofloxacin (OFLX) in patients with severe renal failure (CRF). Saliva OFLX concentration correlated closely with serum OFLX concentration as shown in healthy subjects, although it was significantly lower (about three-quarters), indicating that OFLX had less penetration into saliva in patients with renal failure. Saliva concentration was almost equal to serum concentration during hemodialysis, which might have been due to the constant dialysis of OFLX. In conclusion, saliva concentration was useful for TDM of OFLX in patients with CRF, as it is in healthy subjects.

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Intracellular free calcium concentration ( [Ca²⁺] i) was examined in the platelets of 15 control subjects (NT), 6 predialysis patients with chronic renal failure (CRF), 17 patients on hemodialysis (HD), 20 patients on continuous ambulatory peritoneal dialysis (CAPD), 10 normotensive persons with genetic hypertension (GHT) and 8 essential hypertensive patients (EHT). Levels of (Ca²⁺) i in the platelets were measured by the fluorescent calcium indicator Fura-2. Resting (Ca²⁺) i in CRF and HD patients was higher than the value in NT and that in CAPD patients was similar to NT. rHuEPO significantly increased the level of (Ca²⁺) i in CRF and HD patients compared to those in NT. Under resting and EPO-stimulated conditions, the levels of (Ca²⁺) i in GHT and EHT were higher than those in NT. rHuEPO increased the levels of (Ca²⁺) i in the absence of extracellular calcium in NT, GHT and EHT. In addition, EPO-stimulated calcium influx in GHT and EHT was greater than that in NT. Thus, it appears that the mechanism of rHuEPO-induced hypertension may be mainly due to elevation of (Ca²⁺) i. EPO may contribute to the development of genetic hypertension.

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Prevention of peritoneal function is a major critical factor in the continuation of CAPD treatment. Eightynine CAPD and APD patients were investigated for 7 years or 9 months, respectively. The purpose of the present study was (a) to determine the levels of solute in the blood, i. e. serum creatinine (s-Cr), BUN, hANP, Lp (a) and electroeytes, and urinary volume, water removal and dextrose contents in the dialysate, and (b) to analyze these parameters according to categories such as sex, age, presence of DM and frequency of peritonitis in such patients. Peritoneal function of 15 APD patients was also examined by peritoneal equilibra0ion test (PET) and urea kinetics. Excretion of urine in female CAPD patients was higher than that in male patients. The levels of BUN and s-Cr in male CAPD patients increased gradually during the clinical course due to systemic muscular volume and/or loss of urinary excretion. Although there were no significant changes in the levels of solute in the blood between the ages of more or less than 65 years of CAPD patients, the residual renal function rapidly declined in patients more than 65 years of age. CAPD patients who had DM showed a rapid decline in urinary volume, and an increase in Lp (a) and ultrafiltration. The patients who ad a frequent episode of peritonitis showed a decrease in water removal with increase in the concentration of dextrose in dialysate. There was a significant correlation between the levels of Ccr and those of KT/V in APD patients after the correction of KT/V with dwell time of dialysate storage in the abdominal cavity. It appears that several factors, such as sex, age, presence of DM and frequency of peritonitis, may be important factors in the maintenance of CAPD for long periods.

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We repor here a nine-year-old boy with oligomeganephronia. The patient had proteinuria and morphometric analysis of the renal biopsy specimen confirmed the diagnosis of oligomeganephronia. We employed a color image analyzer (OLYMPUS Corp.) to determine the glomerular surface area and the number of glomeruli per mm² of the renal cortex of the patient. All the scanned glomeruli showed marked hypertrophy; the mean maximal surfacearea for the 5 glomeruli was 46×10³μm2, which is approximately 4 times larger than that of normal children of the same age. The number of glomeruli per mm² of the renal cortex of the patient had decreased to 1.11 per mm², which is approximately one fourth that of normal controls with IgA glomerulonephritis. The color image analyzer proved to be useful for the diagnosis of oligomeganephronia enabling the quantitative measurement of the glomerular surface area and the number of glomeruli per mm² of the renal cortex.uantitative measurement of the glomerular surface area and the number of glomeruli per mm² of the renal cortex.

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We report a case of IgA nephropathy associated with renal hypouricemia. The patient's renal function had decreased gradually during the previous 15 years, resulting in chronic renal failure. Levels of serum uric acid and uric acid clearance were 1.0 mg/dl and 39.4 ml/min, respectively. Pyrazinamide suppression test indicated that the patent had defective tubular reabsorption of uric acid at the presecretory site. The serum uric acid level elevated linearly to 5.0 mg/dl during the 15-year period, in parallel with a change in serum creatinine level, giving a significantly positive correlation coefficient of 0.9776. The ratio of uric acid and creatinine clearances showed no significant change, although both decreased during the 15 years. These results were a different from those in patients with chronic glomerulonephri tis, including IgA nephropathy, where the serum uric acid level had shown no significant correlation with serum creatinine level above 2, 0 mg/dl and the ratio of uric acid clearanceand creatinine clearance had exponentially elevated after the latter decreased below 30-40 ml/min. The patient presented here has defective tubular transport of uric acid at the site of urate reabsorption, and appears to show a different tubular dysfunction response from patients with chronic glomerulonephritis and decreased renal function.

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In recent years, several laboratories have suggested that chronic hepatitis C virus (HCV) infection is strongly associated with type II cryoglobulinemia (CG) and/or membranoproliferative glomerulonephritis (MPGN). We report here a case of MPGN due to type II CG probably associated with chronic HCV infection, and discuss the pathogenesis and treatment of such cases. A 60-year-old-female was referred to us from a local hospital because of progressive peripheral edema, purpura on the lower limbs, pleural effusion, ascites, hyperten sion, and renal failure. Laboratory findings indicated proteinuria, abnormal urinary sedi ments, normochromic normocytic anemia and azotemia. Other laboratory findings included positive rheumatoid factor, elevated serum IgM, hypocomplementemia and elevated circulat ing immune complexies. Cryoglobulin was detected and found to consist of a mixture of a monoclonal IgM κ with polyclonal IgG. Renal biopsy showed MPGN. These observations suggested a close association between MPGN and type II CG. We did not find any causes of type II CG except for positive HCV antibody and HCV RNA. Therefore, we made the diagnosis of type II CG associated with chronic HCV infection. Symptoms related to CG was responsiveness to steroid, but development of liver dysfunction developed. Treatment with alfa-interferon (α IFN) was added and thereafter, the liver dysfunction improved. However, the serum Cryo level was not reproducibly lowered. While in this case it was unclear whether IFN therapy was beneficial, several reports in addition to the findings of this case suggest a close relation between HCV infection and type II CG and MPGN. We think that performing further investigations on this condition may shed light on the more general problem of the pathogenesis and mechanisms of glomerular and vascular damage in immunologically mediated renal disease.

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