Jiro Uemasu

Epidermal Growth Factor and Endothelin in Cyst Fluid From Autosomal Dominant Polycystic Kidney Disease Cases: Possible Evidence of Heterogeneity in Cystogenesis

We determined the concentrations of immunoreactive epidermal growth factor (EGF), endothelin (ET), and cyclic adenosine monophosphate (cAMP) in cyst fluid from 10 nondialyzed patients with autosomal dominant polycystic kidney disease (ADPKD). The concentrations of ET and cAMP in low-sodium cyst fluid (cyst sodium concentration < 100 mEq/L) were significantly increased compared with those in high-sodium cyst fluid (cyst sodium concentration > or = 100 mEq/L), but the concentration of EGF did not differ between the two. There was no relationship between cyst fluid volume and EGF, ET, cAMP values in ADPKD cases. Significant variations of cyst fluid concentrations of EGF, ET, and cAMP were observed among the patients. However, the differences of these variables between the right and left kidney of the individual subjects were unremarkable. Serum levels of creatinine and urea nitrogen showed significant negative correlations with EGF, but not with ET and cAMP. The present data demonstrate the differences in cytokine activity among cysts in ADPKD cases, suggesting the heterogeneity of cystogenesis along the tubular segments in this particular disease.

Clinical significance of plasma endothelin-1 in patients with chronic liver disease.

To determine the clinical significance of plasma endothelin-1 in chronic liver disease, these levels were measured by radioimmunoassay. The plasma endothelin-1 levels in patients with cirrhosis (N=16) (2.04 ± 0.25 pg/ml) and patients with hepatocellular carcinoma (N=22) (2.23 ± 0.17 pg/ml) increased significantly compared with controls (N=16) (1.17 ± 0.17 pg/ml) and patients with chronic hepatitis (N=11) (1.09 ± 0.19 pg/ml) (P<0.01). The presence of ascites rather than tumor volume was associated with a significant elevation of endothelin-1. Endothelin-1 showed significant negative correlations with parameters of hepatic function, including indocyanine green clearance, serum albumin, and prothrombin time. Although endothelin-1 was not correlated with plasma renin activity and plasma endotoxin, it demonstrated a significant positive correlation with the plasma level of atrial natriuretic peptide (r=0.42,P<0.01). These findings demonstrate that plasma endothelin-1 increased in proportion to the severity of liver damage and may be causally related with the derangement of systemic/renal hemodynamics and fluid and electrolyte homeostasis seen in advanced liver disease.

Increased Plasma Endothelin Levels in Patients with Liver Cirrhosis

Jiro Uemasu, MD, Second Department of Internal Medicine, Tottori University School of Medicine, Yonago 683 (Japan) ü. Fig. 1. Plasma endothelin levels in patients with liver cirrhosis. ment of hepatorenal syndrome. Of particular interest is that endotoxin, which usually increased in the blood of patients with hepatorenal syndrome [5], has been demonstrated to stimulate endothelin release from cultured bovine thoractic endothelial cells [6]. Thus, the contribution of endothelin in the development of hepatorenal syndrome requires further investigations. References Epstein M, Berk DP, Hollenberg NK, et al: Renal failure in patients with cirrhosis. Am J Med 1970;10:565-570. Dear Sir, The hepatorenal syndrome is defined as unexplained renal failure in conjunction with severe liver disease. Because of the preservation of tubular functions such as sodium reab-sorptive capacity and of the absence of obvious renal lesions identical to renal failure, this syndrome is considered to be functional in nature. Basically, decreases in glomerular filtration rate in hepatorenal syndrome had been thought to stem from increased renal vascular resistance [1]. Several potential factors have been addressed in the pathogenesis of this clinical entity, but without persuasive answers. Endothelin, a novel vasoconstrictive pep-tide [2], has recently been highlighted on its clinical implications. Since this peptide produces a powerful renal and systemic vasocon-striction [3], such effects may mediate the development of renal failure in patients with severe liver disease. Thus, we determined the plasma endothelin levels in patients with liver disease. Nine cirrhotics with ascites [decomp-ensated; mean age ( ± SEM) 63 ± 4 years] and 9 patients without ascites (compensated; 57 ± 5) and age-matched control subjects (57 ± 5) were studied. Plasma endothelin levels were measured by radioimmunoassay. The results are shown in figure 1. In compensated patients, the plasma endothelin levels (1.27 ± 0.15 pg/ml) were significantly higher compared with the control subjects (0.67 ± 0.11). Decompensated cirrhotics demonstrated further elevations in plasma endothelin levels (1.63 ± 0.13), though there was no statistical change of plasma endothelin levels between the two groups.

ASSOCIATION BETWEEN ANGIOTENSIN CONVERTING ENZYME GENE POLYMORPHISM AND CLINICAL FEATURES IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

We investigated the association between angiotensin converting enzyme (ACE) gene polymorphism and clinical manifestations in 47 patients with autosomal dominant polycystic kidney disease (ADPKD). One-hundred, age- and sex-matched subjects with non-ADPKD served as the controls. ACE gene polymorphism was analysed using a GeneAnp kit. Renal size was determined by abdominal CT scan, by adding the longitudinal axis of each kidney. Incidence of extrarenal complication was also examined. Out of 47 patients, 24 patients (51%) were II, 18 (38%) ID and 5 (11%) DD type. The frequencies of the I and D alleles as well as the distributions of ACE genotypes in ADPKD did not differ from those in controls. The number of patients undertaking renal replacement therapy was 11 in II (46%), 6 (33%) in ID and 2 (40%) in DD genotype, respectively, that was not significantly different among the groups. The mean age of the initiation of renal replacement therapy did not vary among the three genotypes. The slopes of 1/serum creatinine did not differ between II and ID genotypes, whose initial serum creatinine levels ranged from 1.5 to 2.5 mg/dl. Renal size, blood pressure, and extrarenal complications including liver cysts and cardiac valvular disease were unrelated to the ACE genotypes. The present data suggested the irrelevance of ACE gene polymorphism in clinical manifestations in patients with ADPKD.

Cyst sclerotherapy with minocycline hydrochloride in patients with autosomal dominant polycystic kidney disease

BACKGROUND The enlarged cysts in autosomal dominant polycystic kidney disease (ADPKD) frequently cause abdominal discomfort. Cyst sclerotherapy with minocycline hydrochloride was performed to relieve this symptom. METHODS Ten symptomatic ADPKD cases were recruited. As a sclerosant, minocycline hydrochloride solution (10 mg/dl) was used. This solution was instilled into the cysts under ultrasonographic control. Renal volume was calculated before therapy and at 6-month intervals thereafter. Renal function and blood pressure were regularly monitored. The effect of sclerotherapy on symptoms was also assessed at 6-month intervals. RESULTS At 6 months, renal volume was statistically lower than the presclerotherapy, and was associated with improvement in chronic symptoms. However, such ameliorating effects were blunted at 12 months. Renal volume reduction at 6 and 12 months showed a significant positive correlation with the dose of minocycline injected. No significant influence in renal function and blood pressure was observed. CONCLUSIONS These results suggest that cyst sclerotherapy with minocycline hydrochloride is a valid treatment regime for the relief of chronic symptoms in ADPKD cases, although repeated application of this approach may be required to obtain a more long-term effect.

Suppression of plasma endothelin-1 level by a α-human atrial natriuretic peptide and angiotensin converting enzyme inhibition in normal men

The effect of synthetic alpha-human atrial natriuretic peptide (alpha-hANP) on plasma endothelin-1 (ET-1) level was examined in 6 healthy subjects. Intravenous infusion of alpha-ANP (0.1 micrograms/kg/min) resulted in significant falls in plasma renin activity and aldosterone, but without effect on ET-1 level. An angiotensin converting enzyme inhibitor, captopril, increased plasma renin activity and decreased aldosterone, respectively. However, plasma ET-1 levels were not modified by captopril. In cases with alpha-hANP infusion after captopril (25 mg, p.o.,), the renin-angiotensin-aldosterone system was further inhibited compared with the first group, and ET-1 at 60 min was significantly suppressed from the baseline. These data suggest that alpha-hANP when combined with captopril brings about the suppression of plasma ET-1 concentrations in men.

Increased urinary endothelin excretion in patients with liver cirrhosis

The urinary endothelin level in patients with chronic liver disease was determined in order to explore its possible involvement in renal function. The plasma endothelin level was significantly higher in patients with liver cirrhosis (LC) than in those with chronic hepatitis (CH) or in control patients (C). Similarly, urinary endothelin excretion in LC was significantly increased, compared with CH and C. Urinary endothelin demonstrated a significant positive correlation with creatinine clearance. The ratio of endothelin clearance/creatinine clearance did not differ statistically among the three groups. Urinary sodium excretion in LC was positively correlated with plasma endothelin, but not with urinary endothelin. Urinary endothelin excretion demonstrated a significant negative correlation with urinary kallikrein in LC. The present data suggest that increased urinary endothelin excretion in cirrhotic patients primarily depends upon elevated plasma levels of endothelin, but not renal production. Also, a possible link between endothelin and the kallikrein‐kinin system in liver cirrhosis is indicated.

Long-Term Effects of Enalapril in Rat with Experimental Chronic Tubulo-interstitial Nephropathy

The aim of this study was to determine whether or not angiotensin-converting enzyme inhibitor, enalapril, could ameliorate the chronic tubulo-interstitial nephropathy (TIN) in uninephrectomized (UNx) rats. Chronic TIN(M) was induced by 2-bromoethylamine hydrobromide. Rats were assigned to five groups; control, UNx-control (UNxC), UNx treated with enalapril (UNxE), UNxMC and UNxME. Enalapril was given for 12 months as drinking water (50 mg/l). At 6 months, albuminuria in UNxE decreased significantly compared with UNxC, but without change in UNxM rats. By 12 months, although all rats in control, UNxC and UNxE remained alive, 1 and 4 rats died in UNxME and UNxMC, respectively. Albuminuria in UNxC was reduced significantly by enalapril but not in UNxM rats. Both urine volume and urine osmolality became equal to control by enalapril in UNx rats, but not in UNxM rats. Serum cholesterol levels were normalized by enalapril in UNx rats, but not in UNxM rats. Levels of serum creatinine and blood urea nitrogen were invariably higher in UNxM than in UNx rats, irrespective of enalapril. Glomerular sclerosis was statistically decreased by enalapril in both UNx and UNxM rats. Enalapril reduced the overall tubulo-interstitial lesions in UNx rats, but not in UNxM group. However, in UNxM rats tubular changes in medullary portion were significantly ameliorated by enalapril. These data suggest that enalapril has a beneficial effect on chronic TIN in this model.

Effects of a Rice Meal on Renal Hemodynamics and Excretory Functions in Normal Subjects

The nature of renal hemodynamic response to a large carbohydrate-rich meal and the associated renal excretory functions were examined. Seven normal subjects were studied after ingestion of 300 g of rice meal. Five healthy men served as a time control. After eating the test meal, the mean creatinine clearance began to rise and became significantly higher in the 2nd hour compared with the control (118 +/- 7 vs. 91 +/- 3 ml/min/1.73 m2; p less than 0.01). Urinary excretion rates of sodium and chloride after the meal were significantly higher compared with those in the premeal period. Blood glucose concentrations rose significantly following the meal. The postprandial plasma levels of amino acids did not vary significantly compared with the premeal values. These results demonstrate that rice meal ingestion increased glomerular filtration rate via a mechanism(s) different from the protein-induced glomerular hyperfiltration.

Biochemical characteristics of cyst fluid in undialysed patients with autosomal dominant poiycystic kidney disease

Summary: The biochemical composition of cyst fluid was analysed in 148 cysts obtained from 10 patients with autosomal dominant polycystic kidney disease (ADPKD). Serum creatinine levels ranged from 1.7 to 9.0 mg/dL. No patients were receiving renal replacement therapy. Aspirated cyst volume ranged from 4‐120 mL. There was no significant correlation between cyst volume and cyst sodium concentration ([Na]cyst). Cyst sodium concentration demonstrated a bimodal distribution pattern, with one peak from 10‐20 mEq/L and the other from 140‐150 mEq/L. the ratios of cyst fluid versus serum sodium concen tration ([Na]cyst/serum) were positively correlated with [C1]cyst/serum, while negatively correlated with [K]cyst/serum, [Ca]cyst/serum, [P]cyst/serum and [UA]cyst/serum. Based on the [Nalcyst/serum, the cysts were assigned to three types: proximal (0.8‐1.4), indeterminant (0.4–0.8) and distal (<0.4). the percentage of each type was 54.7, 19.6 and 25.7%, respectively. There were no significant differences in [Na]cyst/serum between the right and left kidney in individual patients. the concentrations of amino acids were higher in the distal type than in the proximal type.