Urinary excretion of enzymes in cirrhotics with renal failure

We studied the significance of urinary enzyme measurements in diagnosing proximal tubular damage in cirrhosis of the liver. Urinary excretion (u-enzyme) and fractional urinary excretion (FEenzyme) of gamma-glutamyltranspeptidase (GGT), leucine aminopeptidase (LAP), alkaline phosphatase (AP) and beta-glucuronidase (B-GLU) were quantified in 14 control subjects (group I), 12 cirrhotics with functional renal failure (group II), 13 cirrhotics with renal tubular damage (group III) and 7 non-liver patients with renal tubular damage (group IV). Urinary enzyme excretion and fractional enzyme excretion were significantly higher in the cirrhotics of group III than in the controls or group II. In group III, these tests usually reached values within the range of group IV. The sensitivity of urinary enzyme excretion was 0.92 and specificity ranged from 0.75 (u-LAP) to 1 (u-GGT; u-B-GLU). The sensitivity of fractional enzyme excretion was between 0.61 (FEB-GLU) and 0.84 (FEGGT; FELAP), while specificity was from 0.91 (FELAP; FEAP) to 1 (FEGGT; FEB-GLU). The results indicate that measurement of urinary enzymes may be very useful in diagnosing renal tubular damage in cirrhotic patients with impaired renal function.     

Tense ascites redefined: renal consequences of tense ascites in decompensated cirrhotics.

Cirrhotics with tense ascites fail to achieve increased diuresis in the supine position. To assess the role of inferior vena cava compression in this phenomenon, we studied cirrhotics with mild to moderate (n = 11) and tense (n = 2) ascites, and patients with membranous inferior vena cava obstruction (n = 2) before and after balloon dilatation, in the sitting, supine and 10 degrees head down tilted positions for 2 hours each. Urinary output (p < 0.005), creatinine clearance (p < 0.025) and sodium excretion (p < 0.025) increased in cirrhotics with mild to moderate ascites in the supine position, and further in the head down position. Similar changes occurred in patients with inferior vena cava membrane. In cirrhotics with tense ascites, these parameters did not change significantly in the supine position, but increased in the head down position. We conclude that failure to augment diuresis in the supine position in cirrhotics with tense ascites is not due to inferior vena cava obstruction alone but is probably also due to compression of the collateral vessels. This clinical observation may serve as a criterion for diagnosing tense ascites.     

Renal kinin and kallikrein excretion in cirrhotic patients

Urinary kinin and urinary kallikrein activity were measured in 33 liver cirrhotics, and the values were correlated with the severity of the liver disease. A significant relationship was observed between urinary kinin excretion and urinary kallikrein excretion (r = 0.53; p less than 0.01). Both urinary kinin and kallikrein excretion were significantly lower in Child's group C than in Child's groups A and B (p less than 0.05) and showed positive correlations with serum albumin (r = 0.47, p less than 0.01 and r = 0.46, p less than 0.01, respectively). Increases in urinary kinin and kallikrein excretion after endoscopic variceal sclerotherapy were observed in 18 patients (p less than 0.01 and p less than 0.05, respectively). These results suggest that the renal kallikrein-kinin system in suppressed in severe liver disease in proportion to the severity of the underlying liver disease. In this study possible activation of this system after sclerotherapy was also demonstrated.     

Transjugular intrahepatic portosystemic shunting improves splanchnic hemodynamics and renal Na excretion in cirrhosis with refractory ascites

To clarify the pathogenesis of ascites in patients with liver cirrhosis, we explored the effects of transjugular intrahepatic portosystemic shunting in six cirrhotic patients with refractory ascites. The portal pressure decreased from 39 ± 7 cmH₂O before treatment to 32 ± 5 cmH₂O immediately after the procedure. Liver function transiently deteriorated after the procedure, but recovered within 1 week. Urinary Na excretion increased 1 week after treatment. In five patients, ascites improved within 3 weeks. Along with the decrease of portal congestion, there was an improvement of esophageal varices, and an increase of gastric mucosal blood flow, and an inhibition of the renin-angiotensin-aldosterone system in all of the patients after 2–4 weeks. Manageable shunt encephalopathy occurred in three patients. These findings strongly suggest the pivotal role of increased portal pressure in the formation of ascites in patients with liver cirrhosis.     

Relationship of urinary kallikrein excretion to renal water and sodium excretion

The circadian rhythms of urine volume and urinary excretion of sodium, potassium, kallikrein, and aldosterone were analyzed by a multivariate method (cosinor method) in 20 healthy Japanese women on an ordinary diet. The relationship of urinary kallikrein and aldosterone excretion to urine volume and urinary sodium and potassium excretion was studied by assessing the correlation of the circadian rhythms. The acrophases in the circadian rhythms of urine volume (16:51) and urinary sodium excretion (16:55) appeared after the acrophase of urinary kallikrein excretion (15:28). There was a highly significant correlation between the circadian rhythm of urinary kallikrein excretion and the circadian rhythms of urine volume (r = 0.948) and urinary sodium excretion (r = 0.921). These results suggest that the renal kallikrein-kinin system participates in the regulation of renal water and sodium excretion in persons on an ordinary diet. A highly significant relationship between the acrophases in the circadian rhythms of urine volume and sodium excretion (r = 0.935) also suggests that water and sodium excretion may have a mutual influence on the kidneys. There were positive correlations between the circadian rhythms of potassium excretion and kallikrein excretion and potassium excretion and sodium excretion; and the latter relationship was relatively closer than the former. The acrophase in the circadian rhythm of aldosterone excretion did not correlate well with the acrophases of the other urine variables including sodium excretion.     

Renal hemodynamics and water excretion in Addison's disease.

Patients with Addison's disease have impaired ability to excrete free water. The mechanism of this defect is still not clear. These experiments were designed to help clarify the role of altered renal hemodynamics in the genesis of the defect. Six patients with Addison's disease were studied. Enough salt and water was administered to maintain adequate hydration throughout the study but no hormonal replacement was instituted. After a water load, the urine output (V), free water clearance (CH2O), sodium excretion (UNaV), total solute clearance (COsm), inulin clearance (CIn), and para-aminohippurate clearance (CPAH) were measured by standard clearance techniques. In the control studies V and CH2O were abnormally low. The studies were repeated after administration of DOCA, 2.5 mg daily, for a week. This medication decreased UNaV and improved the plasma electrolyte profile but did not cause a significant change in V, CH2O, GFR, or RPF. The same studies were repeated once more after administration of prednisone, 5 mg daily in divided doses, for a week. This drug induced a marked water diuresis while GFR and RPF remained unchanged. It is concluded that hypovolemia and altered renal hemodynamics are not the only mechanisms of the impaired water excretion in Addison's disease. A severe defect remains after normalization of hypovolemia and this is corrected by prednisone but not by DOCA, through mechanisms which do not involve changes in GFR or RPF.     

Urinary kallikrein excretion in insulin-dependent diabetes mellitus and its relationship to glycemic control

The renal kallikrein-kinin system is thought to be involved in vasoregulatory and epithelial ion-transporting processes. Renal kallikrein has not been studied in patients with diabetes mellitus, a disease in which abnormalities of renal hemodynamics and electrolyte handling occur. The urinary excretion of this kallikrein was measured in 20 type I diabetic patients and 10 normal subjects. On a 120-meq Na diet, daily kallikrein excretion, determined by both esterase activity and direct RIA, in 12 poorly controlled diabetic patients [hemoglobin A1c (HbA1c) = 14.2 +/- 0.5% (mean +/- SEM)] was significantly greater (P less than 0.05) than excretion in 8 diabetic patients in good to moderately good control (HbA1c = 9.4 +/- 0.5%) or in 10 normal subjects. In these groups, urinary esterase activities were 9.4 +/- 1.0, 6.1 +/- 1.4, and 6.7 +/- 0.5 esterase units/24 h, respectively. Corresponding excretion values of immunoreactive kallikrein were 171 +/- 14, 118 +/- 26, and 123 +/- 11 micrograms/24 h. Creatinine clearances were similar in the three groups. Urinary kallikrein was also measured in 8 diabetic and 8 normal subjects during 7 subsequent days of 10 meq Na intake. It increased less in diabetic patients than in normal subjects during Na depletion (P less than 0.02). The increase in urinary kallikrein in the diabetic patients was inversely related to their HbA1c levels (r = 0.88; P less than 0.01). The effect of glycemic control on urinary kallikrein excretion was determined in nine diabetic patients. Initial glycemic control was achieved using an artificial endocrine pancreas (Biostator) and was maintained by continuous sc insulin infusion with a portable pump. Before glycemic control, urinary kallikrein was 190 +/- 30 micrograms/24 h (by RIA). After 8-12 days of glycemic control, excretion fell to 144 +/- 23 micrograms/24 h (P less than 0.02). The abnormalities in kallikrein excretion in diabetic patients were not correlated with differences in water, electrolyte, protein, glucose, or aldosterone excretion in any of the studies. These results show that kallikrein excretion was increased in patients with poorly controlled insulin-dependent diabetes, and excretion rose less in diabetic subjects with low Na intake than in normal subjects. Strict glycemic control decreased urinary kallikrein excretion. These findings suggest that the renal kallikrein-kinin system is functioning abnormally in diabetes mellitus.     

Urinary kallikrein excretion after renal transplantation: Relationship to hypertension,graft source,and renal function

The role of the renal kallikrein-kinin system in the pathogenesis of hypertension and various forms of renal dysfunction after human renal transplantation has been assessed by measurement of urinary kallikrein activity in 41 renal transplant recipients. The urinary tosyl arginine methyl esterase assay was used. The urinary kallikrein in these patients appeared to originate from the transplanted kidney and not their own diseased kidneys. Twenty-three recipients had hypertension (mean blood pressure 156 ± 3/98 ± 2 mm Hg) and excreted less kallikrein (4.0 ± 1.2 versus 12.5 ± 4.0 esterase units [EU] per 24 hours, p < 0.05) than their 18 normotensive counterparts (mean blood pressure 132 ± 2/77 ± 1 mm Hg, both p < 0.01). Subjects with renal complications of transplantation (acute tubular necrosis [ATN], nine patients, or acute rejection [AR], eight patients) also excreted less kallikrein than the 28 subjects without such complications (3.4 ± 0.9 versus 10.3 ± 2.7 EU/24 hours, p < 0.02). Among those with acute renal complications, subjects with ATN excreted less kallikrein than those with AR (1.3 ± 0.3 versus 5.7 ± 1.7 EU/24 hours, p < 0.02). Cadaver graft recipients excreted less kallikrein than living related donor graft recipients (2.1 ± 0.4 versus 13.0 ± 3.5 EU/24 hours, p < 0.01), perhaps reflecting their higher blood pressures (mean systolic pressure 151 ± 3 versus 140 ± 3 mm Hg, p < 0.04), relatively impaired renal function (creatinine clearance values 42 ± 8 versus 62 ± 5 ml/min, p < 0.04), and higher incidence of ATN (nine cases versus none). The kallikrein-kinin system may be involved in the pathogenesis of hypertension and some forms of renal dysfunction after renal transplantation.     

Uric acid: Its relationship to renal hemodynamics and the renal renin-angiotensin system

Reports relating hyperuricemia and hypertension have been fieled for many decades. Nevertheless, controversy remains concerning serum uric acid concentration as an independent risk factor underlying coronary heart disease (CHD) and essential hypertension or as an indirect marker of renovascular involvement. Earlier studies in normotensive subjects and hypertensive patients demonstrated that serum uric acid concentration was closely related to intrarenal hemodynamic alterations, suggesting that it is an excellent marker of vascular involvement. Our data from clinical studies and in an animal model of severe hypertensive nephrosclerosis have strengthened this concept. Conversely, other reports have suggested that uric acid may be a pathogenetic factor. Supporting arguments for this theory maintain that experimental hyperuricemia induces hypertension and renal damage. Epidemiologically, hyperuricemia is associated with hypertension, CHD, renal disease, toxemia of pregnancy, and other outcomes, although mechanisms remain unclear. Additionally, there are no available data on the effects of lowering uric acid on pressure control and organ protection.     

Total paracentesis in non-alcoholic cirrhotics with massive ascites: Mid-term effects on systemic and hepatic haemodynamics and renal function

Single total paracentesis (4.8–11 L) was performed in 23 patients with hepatitis B surface antigen (HBsAg)-positive cirrhosis and massive ascites and its effects on systemic and hepatic haemodynamics and renal function were examined over 5 days. Severe hypotension occurred in six (26.1%) patients from 6 to 54 h after paracentesis. In the remaining 17 patients, compared to the baseline, there was an increase in the cardiac output (6.1 ± 0.3 vs 6.7 ± 0.3 L/min, P <0.001) and a decrease in right atrial pressure (8.8 ± 0.8 vs 4.3 ± 0.7 mmHg, P <0.001), systemic vascular resistance (1160 ± 61 vs 976 ± 50 dyne·s·cm ^?5, P <0.001), and wedged hepatic venous pressure 30 min after completion of paracentesis. After 5 days, right atrial pressure, systemic vascular resistance and wedged hepatic venous pressure returned to baseline, while the cardiac output dropped to a level lower than the baseline (5.7 ± 0.7 L/min, P<0.05). Hepatic venous pressure gradient had returned to baseline after 5 days. Serial tests of serum creatinine level showed an increase from day 3 (1.34 ± 0.14 vs 1.04 ± 0.10 mg/dL, P <0.05). On day 5, creatinine clearance (55.7 ± 5.4 vs 41.9 ± 5.3 mL/min, P <0.05) and effective renal plasma flow (351 ± 32 vs 293 ± 29 mL/min, P <0.05) were decreased, compared to the baseline. Based on these data, infusion of a volume expander may be necessary for total paracentesis to avoid systemic haemodynamic complications in non-alcoholic cirrhosis.     

Peritoneal fibrosis in cirrhotics treated with peritoneovenous shunting for ascites

Of 554 cirrhotics autopsied during 1975–1993, 69 had had peritoneovenous shunts. Generalized peritoneal fibrosis with cocoon formation was found in 26 (38%) of those with shunts but in only one of 485 without shunts (P=0.00002). In 14/26 the fibrosis was asymptomatic, an incidental autopsy finding. Intestinal obstruction in 12/26 (46%), the only symptomatic manifestation, was fatal in five. The etiology of peritoneal fibrosis in shunted patients is unknown. The 26 patients with fibrosis had more prior abdominal operations, complicated abdominal wall hernias, and active biliary tract inflammations; these features differentiated them from the 43 patients without fibrosis. Scores in a peritoneal complication index, that considered multiple risks in the same patients, were significantly higher in those with fibrosis. In addition to these peritoneal injuries or inflammations, the faster ascitic fluid circulation in shunted patients may have increased deposition of fibrin upon the peritoneum. Fibrogenic cytokines, thus spread throughout the abdomen from local sites, may have converted fibrinous adhesions to generalized peritoneal fibrosis.Supported by the Department of Veterans Affairs Medical Research Service.     

Immediate effects of furosemide on renal hemodynamics in chronic liver disease with ascites

Furosemide occasionally causes azotemia in patients with ascites, independently of induced volume depletion. To define this effect, we measured renal clearances in patients with chronic liver disease and ascites and in nonascitic controls. Furosemide (80 mg i.v.) transiently increased p-aminohippurate clearance in controls (from 693 +/- 67 to 928 +/- 93 ml/min) and in 11 patients with ascites (from 418 +/- 81 to 526 +/- 80 ml/min). In contrast, in 13 patients with ascites, p-aminohippurate clearance fell by 34% (from 545 +/- 51 to 360 +/- 24 ml/min) within 20 min and by 41% within 60 min, and inulin clearance fell by 19% at 20 min and by 30% at 60 min. The renal effects lasted approximately 4 h. The renal response could not be predicted by renin activity, urinary prostaglandin excretion, urinary sodium, or clinical characteristics. In all 14 patients who received oral furosemide, p-aminohippurate clearance fell within 90 min (by 24%) and remained suppressed for at least 4 h. These immediate effects of furosemide on renal perfusion may contribute to azotemia in some patients with ascites.     

Renal hemodynamics and pharmacokinetics of bevantolol in patients with impaired renal function

The effects of bevantolol on renal blood flow and glomerular filtration rate and the drug's pharmacokinetics were studied for 7 days in 18 patients (mean age 50 years) with varying degrees of renal dysfunction. Patients were divided into 3 groups: group 1 had a creatinine clearance of 50 to 80 ml/min, group 2, 20 to 49 ml/min and group 3, less than 20 ml/min. After baseline inulin and paraaminohippuric acid clearance values were obtained, patients were given a single, 150-mg "priming" administration of bevantolol. The kinetics of the drug (including plasma drug levels, plasma half-life and plasma clearance) and its effects on renal function were observed for 24 hours. On days 4 to 6 of the study, patients received 150 mg of bevantolol twice daily, with only a single dose given on day 7. Bevantolol did not significantly affect either inulin or paraaminohippuric acid clearance in patients with differing degrees of renal function. In 50% of patients with a creatinine clearance of less than or equal to 50 ml/min, both the half-life and maximum trough serum levels were higher than the ranges seen in healthy subjects. However, neither value appears to be clinically relevant because bevantolol has a wide therapeutic range. Renal impairment did not change the percentages of the bevantolol dosage excreted unchanged or as conjugated drug in the urine, and no toxic or active drug metabolites accumulated in the blood. From these results, it appears that bevantolol may be used safely in short-term therapy of patients with renal impairment.     

Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension

Increased renal resistive index and urinary albumin excretion are markers of hypertensive end-organ damage and renal vasoconstriction involving increased sympathetic activity. Catheter-based sympathetic renal denervation (RD) offers a new approach to reduce renal sympathetic activity and blood pressure in resistant hypertension. The influence of RD on renal hemodynamics, renal function, and urinary albumin excretion has not been studied. One hundred consecutive patients with resistant hypertension were included in the study; 88 underwent interventional RD and 12 served as controls. Systolic, diastolic, and pulse pressure, as well renal resistive index in interlobar arteries, renal function, and urinary albumin excretion, were measured before and at 3 and 6 months of follow-up. RD reduced systolic, diastolic, and pulse pressure at 3 and 6 months by 22.7/26.6 mm Hg, 7.7/9.7 mm Hg, and 15.1/17.5 mm Hg (P for all <0.001), respectively, without significant changes in the control group. SBP reduction after 6 months correlated with SBP baseline values (r=-0.46; P<0.001). There were no renal artery stenoses, dissections, or aneurysms during 6 months of follow-up. Renal resistive index decreased from 0.691±0.01 at baseline to 0.674±0.01 and 0.670±0.01 (P=0.037/0.017) at 3- and 6-month follow-up. Mean cystatin C glomerular filtration rate and urinary albumin excretion remained unchanged after RD; however, the number of patients with microalbuminuria or macroalbuminuria decreased. RD reduced blood pressure, renal resistive index, and incidence of albuminuria without adversely affecting glomerular filtration rate or renal artery structure within 6 months and appears to be a safe and effective therapeutic approach to lower blood pressure in patients with resistant hypertension.     

Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites

Circulating levels of endotoxin, interleukin (IL)-6, and tumor necrosis factor (TNF)-α increase with intestinal bacterial overgrowth and translocation, and are believed to be involved in the pathogenesis of hyperdynamic circulatory syndrome and functional renal failure in patients with advanced cirrhosis. We investigated the effects of the antibiotic rifaximin on systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. We measured mean arterial pressure, cardiac output (CO) by Doppler ultrasound, systemic vascular resistance (as the ratio of mean arterial pressure:CO), plasma renin activity, levels of plasma aldosterone, the glomerular filtration rate by plasma clearance of technetium-99m-DTPA, natriuresis, levels of plasma endotoxin, and serum levels of IL-6 and TNF-α in 13 patients at baseline and after 4 weeks of treatment with rifaximin. Rifaximin treatment significantly reduced CO and significantly increased systemic vascular resistance, in association with a significant decrease in plasma rennin activity. The therapy also significantly increased the glomerular filtration rate and natriuresis while reducing levels of endotoxin, IL-6, and TNF-α. Intestinal decontamination with rifaximin improved systemic hemodynamics and renal function in patients with advanced cirrhosis.