Intestinal Dialysis Research Articles

A Forty Year History 1960–2000

A Forty Year History 1960–2000

Activated charcoal interrupts enteroenteric circulation of phenobarbital.

The possibility of activated charcoal interrupting the enteroenteric circulation of phenobarbital was conducted in rabbits prepared by colectomy biliary drainage to block enterohepatic circulation. Fifty minutes after the administration of phenobarbital IV over ten minutes, activated charcoal (N = 7) or non-adsorbent gel (N = 8) were placed into the intestine at a dose of 4 g/kg. Blood was taken hourly for 5 h from the femoral artery and portal vein for the determination of phenobarbital concentration by the homogeneous enzyme immunoassay. The arterio-portal differences of phenobarbital concentrations were significantly greater in the animals treated with the charcoal at 2, 3 and 4 h after the treatment. There were significantly shorter plasma half lives of phenobarbital in the animals given charcoal (3.8 +/- 0.3 h vs 6.9 +/- 0.9 h, p < .02). This study provided evidence of significant enteroenteric circulation of phenobarbital which can be interrupted by the activated charcoal and removed by the mechanism of intestinal dialysis.

Effect of Ethanol Perfusion on Creatinine Removal in a Roux-Y Intestinal Segment

Five rats and 2 goats had a bypass operation to allow infusion of sorbents through an inlet ostomy. The sorbents passed through one limb of intestine isolated from food contact to join a food limb which included 30-40% of the original length of small intestine. In goats, serum creatinine levels were elevated by infusion of sterile creatinine solutions intravenously. Twenty-four hour urines were collected before, during and after periods of infusion of sorbents into the inlet ostomy. Infusion of charcoal into the ostomy had little effect on the total daily urinary creatinine excretion (TDUC). However infusion of 4.3 g/kg/day ethanol decreased the TDUC significantly, in both species. In rats, 8.6 g/kg/day ethanol infusion had an even greater effect on TDUC. Studies of intraluminal creatinine concentration in the distal part of the sorbent segment indicated that especially when serum concentration of creatinine is over 2 mg%, ethanol greatly increases the intraluminal creatinine concentration in the intestine. It is concluded that ethanol, in combination with intestinal sorbents or alone, could allow intestinal dialysis to remove considerably more creatinine, and possibly aid transport of other organic substances.

Continuous Intestinal Dialysis for Uraemia by Intermittent Oral Intake of Non-Absorbable Solutions: An Experimental Study

A new approach to intestinal dialysis was investigated in a normal person and in a patient with chronic uraemia and a renal creatinine clearance of 10 ml/min. Both subjects drank 1-1.5 l non-absorbable solutions of polyethylene glycol or mannitol every fourth hour. The solutions stayed in the intestines for about four hours in the normal person and for 1.5 to 3 hours in the patient. The patient's intestinal clearances were 6-10.4 ml/min for creatinine, 4 ml/min for uric acid and 10.7-15.4 ml/min for phosphate, which compares favourably to those from 12 hours weekly haemodialysis. Continuous intestinal dialysis was well tolerated and the results indicate that this might be a useful way of treating uraemia if conventional methods are unavailable.

Pharmacokinetics of theophylline and phenobarbital during peritoneal dialysis compared with intestinal dialysis in rats.

The transfer rates of theophylline and phenobarbital from blood into the peritoneal cavity were investigated after their intravenous administrations at a dose of 10 mg/kg each in rats. Appreciable amounts of both drugs were transported into the dialysate with their transfer rates decreasing as the serum concentrations declined. The average amount of theophylline transferred into the dialysate was 17% and 24% of dose in 2 and 4 h, respectively, while that of phenobarbital was 13% and 45% of dose in 2 and 8 h, respectively. The amounts appeared to be greater than those transported into the intestinal lumen which was previously reported by the authors. Peritoneal dialysis decreased the serum half-life and the area under the serum concentration-time curve (AUC) value of theophylline from 2.1 to 1.5 h and from 38 to 26 micrograms.h/ml, respectively and increased the total body clearance by 47% as compared with the control. The dialysis also decreased the serum half-life and the AUC value of phenobarbital from 8.3 to 5.3 h and from 116 to 83 micrograms.h/ml, respectively and increased the total body clearance by 112% as compared with the control. Overall, the effectiveness of peritoneal dialysis in removing theophylline and phenobarbital appears to be not very different from that of intestinal dialysis with oral activated charcoal which has been previously reported by the authors in spite of the difference in transport into the intestinal lumen and peritoneum.

Transport of procainamide and N-acetylprocainamide from blood into the intestinal lumen and intestinal dialysis by oral activated charcoal in rats with acute renal failure.

The characteristics of exsorption and/or excretion of procainamide and its metabolite, N-acetylprocainamide (NAPA), into the small intestinal lumen in both normal rats and rats with acute renal failure (ARF rats) induced by uranyl nitrate were investigated by an in situ single-pass perfusion technique. The exsorption of procainamide and NAPA from blood into the intestinal lumen was increased in ARF rats compared with normal rats. The mean apparent renal, biliary and intestinal clearance values of procainamide were 186, 1.83 and 73.9 ml/h/kg in normal rats, respectively, and were 2.02, 1.37 and 55.8 ml/h/kg in ARF rats respectively. Furthermore, the mean renal, biliary and intestinal clearance values of NAPA were 35.2, 19.4 and 21.1 ml/h/kg in normal rats, respectively, and were 1.12, 21.0 and 26.0 ml/h/kg in ARF rats, respectively. There was little difference in the intestinal clearance values of procainamide and NAPA between normal and ARF rats. The ratio of nonrenal clearance/total body clearance was greater in ARF rats than in normal rats. Treatment with oral activated charcoal reduced the serum NAPA levels in both normal and ARF rats, and had little effect on the serum procainamide levels in normal rats, while it reduced the serum drug levels in ARF rats. Consequently, the increase in both drugs transported into the intestinal lumen induced by renal failure may enhance the intestinal clearance of the drug by oral administration of activated charcoal.

Evaluation of orally administered activated charcoal on intestinal dialysis of intravenously administered M79175, an aldose reductase inhibitor, in rats.

The effect of oral administration of activated charcoal on serum elimination of 14C-M79175 injected intravenously in rats was studied. In situ single-pass perfusion studies showed that M79175 and/or its metabolites was transported into the small intestinal lumen. Total radioactivity expressed as equivalents of M79175 exsorbed in the perfusate and excreted in the bile juice was 3.2% and 2.0%, respectively, of dose. Oral administration of multiple doses of activated charcoal significantly decreased the serum concentration and serum half-life of 14C-M79175. The fecal excretion of 14C-M79175 after treatment with activated charcoal was increased when compared to that in the control. On the other hand, urinary excretion of 14C-M79175 after treatment with activated charcoal was decreased. However, there was no significant difference in the cumulative amounts of total excretion (fecal plus urinary excretion) between rats with activated charcoal treatment and rats without charcoal treatment. These results suggest that intestinal dialysis by oral activated charcoal is a reasonable method to enhance the elimination of M79175 from the serum in case of overdose of the drug.

The intestinal dialysis of intravenously administered phenytoin by oral activated charcoal in rats.

The effect of oral administration of activated charcoal on total body clearance of phenytoin following intravenous administration was studied in rats. In situ single-pass perfusion study showed that phenytoin was exsorbed into the small intestinal lumen. The exsorption of the drug from blood into the intestinal lumen was increased in a dose-dependent manner. The exsorption rate of the drug at the dose of 10 mg/kg was 1.1% in 120 min, while that at 50 mg/kg was 2.5% in 120 min. The excretion of the conjugate of 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) into the bile was greater than phenytoin and unconjugated p-HPPH and the total percentage of excretion of p-HPPH was significantly decreased by increasing the dose. Oral activated charcoal had little effect on the serum phenytoin levels after the 10 mg/kg dose. On the other hand, charcoal reduced the serum phenytoin levels after the 50 mg/kg dose as compared with the corresponding controls. Oral administration of activated charcoal decreased the serum half-life to 77% and the area under the serum concentration-time curve to 75% after the 50 mg/kg dose of phenytoin. The apparent volume of distribution was not significantly different between rats with activated charcoal treatment and rats without charcoal treatment. Based on these results, a mechanism of the enhanced clearance of phenytoin at a high dose (50 mg/kg) may be due to the adsorption of the drug and its metabolites transported into the gastrointestinal tract by the charcoal.

Accelerated clearance of intravenously administered theophylline and phenobarbital by oral doses of activated charcoal in rats. A possibility of the intestinal dialysis.

The effect of oral administration of activated charcoal on the clearance of theophylline and phenobarbital following their intravenous administration was studied in rats. Oral administration of multiple doses of activated charcoal significantly decreased the serum half-life and AUC (area under the curve) and increased the total body clearance of both theophylline and phenobarbital as compared with their respective controls. The volume of distribution was not significantly different between treatments. A single dose of activated charcoal showed only a slight enhancement of clearance of theophylline. Accelerated clearance of both drugs by oral activated charcoal was rationalized in terms of adsorption of exsorbed drugs and inhibition of their reabsorption by activated charcoal in the gastrointestinal tract.

Improved jejunal loop dialysis using unconjugated bile salts

Perfusion of isolated intestinal loops has been utilized in the management of uremia, although the technique has been limited by an inability to adequately extract creatinine. In a recent study of uremic rats, the addition of sodium deoxycholate (NaDC) to the perfusate increased clearance of sodium and creatinine sevenfold. This investigation was designed to confirm this effect in canines and to determine if increased creatinine excretion can be maintained in the absence of net water flux. Isolated jejunal loops of 38 to 75 cm in length were created in conditioned canines. Following a 2-week recovery period, loops were perfused with control solutions (Na 60 meq/liter, K 8 meq/liter, Cl 65 meq/liter, polyethylene glycol 5 g/liter, adjusted osmolarity 360 mosm/liter), and experimental solutions of comparable composition and osmolarity including 2 m M NaDC. NaDC perfusion increased loop creatinine excretion four- to sevenfold allowing clearances of up to 79 mg of creatinine/hr. This increase was statistically significant ( P < 0.01) when compared to control perfusions (control 6.00 ± 5.16 mg/hr vs NaDC 37.54 ± 16.61 mg/hr). No net water flux and minimal electrolyte flux were noted. Longer loops required higher perfusion rates to maximize creatinine excretion; optimal perfusion rates approximated 40 ml/hr/cm. Bile salts significantly increased creatinine secretion from isolated jejunal loops without obligatory electrolyte or water movement. Addition of such local agents may improve the efficiency of intestinal dialysis and allow reconsideration of clinical use.

Excretion of creatinine into gastrointestinal tract in renal-artery-ligated rats.

Excretion of creatinine into gastrointestinal tract was studied using renal-artery-ligated rats as a model of patients suffering from renal failure. In the rats of first group, both arterial branches of kidney and bile duct were ligated, and a saline solution was sent through the intestinal lumen to perform the intestinal dialysis. In the second group, after ligation of both renal arteries, a fine catheter was sutured with bile duct to collect the bile. After the intravenous administration of creatinine (138 mg or 34 mg/kg) through the femoral vein, the animals were kept for 1 hr until the creatinine level in body-fluid approach to steady state. Under these steady state conditions, about 170 μg or 70 μg of creatinine was permeated into gastrointestinal tract every 1 hr from upper and lower region of jejunal mucosa after the administration of 138 or 34 mg/kg of creatinine, respectively. The creatinine concentration in bile was similar to that in blood and about 200-270 μg or 90-110 μg of creatinine was excreted into bile every 1 hr after the injection of 138 or 34 mg/kg of creatinine, respectively. Creatinine excreted from the intestinal mucosa and bile was collected together by perfusing the saline solution for 3 hr. About 3.5% of creatinine was excreted. These results suggested that, at least, 20-30% of creatinine in body fluid may be excreted daily into gastrointestinal tract through the intestinal mucosa and from bile in the renal shutdown rats.

Intestinal dialysis in experimental animals.

The effect of dialysis of the small and large intestine on serum urea and creatinine levels and on electrolyte and water balance was experimentally investigated in bilaterally nephrectomized miniature pigs. For experiments on the small intestine a segment of terminal ileum approximately one metre long was used. Colonic perfusion was carried out after creating a double-bore transverse colostomy. Potassium-free dialysis fluids were perfused through the isolated intestinal loops at a flow rate of 2 litres per hour. In no instance was intestinal dialysis successful in prolonging life, nor did it produce any effective fall in serum urea and creatinine levels. Colonic perfusion had some influence on hyperkalaemia but small intestinal perfusion was ineffective. Water balance and electrolyte changes were also studied. In conclusion it is emphasized that in the light of these experimental results intestinal dialysis is likely to be of very little clinical value.

Uraemia and its treatment by arginase inhibitor.

URAEMIA is retention of urea in the body, and is due to renal insufficiency. It has been proved beyond doubt that the kidney is the only organ through which urea can be eliminated from the body1. Therefore renal insufficiency of an organic or a functional type will reverse the clearance of urea from the body, with consequent retention. The methods involving intestinal and peritoneal dialysis, artificial kidney and possibilities of a successful kidney homotransplant for the treatment of uraemia are mainly based on the principle of eliminating urea from the body. The problem becomes very much simplified if technique can be evolved checking the synthesis of urea, which obviously could cause least damage to the patient.

Treatment of uremia by perfusion of an isolated intestinal loop; survival for forty-six days after removal of the only functioning kidney.

In 1946, de Leeuw and Kolff¹treated a patient with contracted kidneys and uremia by dialysis through an intestinal loop. A loop of small intestine was separated by transverse sections and the ends brought out through lateral stab wounds, leaving the vasculature intact. The continuity of the remaining intestine was restored by end-to-end anastomosis. The isolated intestinal loop was perfused. Rinsing fluid from a reservoir was let into the proximal end of the intestinal loop after passage through a Murphy drip and through a thermostatically controlled bath to bring it up to body temperature. From this first patient 5 gm. of urea could be removed in 10 hours of perfusion. Since then, all our patients with severe chronic uremia were treated with a forced high-caloric, low-protein diet according to the principle of Borst. Conditions demanding intestinal dialysis rarely occurred. Odel and Ferris,²Seligman, Frank and Fine,³and

Congestive heart failure of renal origin: Pathogenesis and treatment in four cases of carbon tetrachloride nephrosis

ECENT interest has been focused on R a clinical-pathologic syndrome of varied etiology characterized by severe oliguria and uremia and classified under the heading of lower nephron nephrosis.’ Numerous reports of this condition in the past few years have been concerned predominantly with the pathogenesis and pathologic physiology of the renal disturbancee7 or with therapeutic technics to clear the blood of retained waste products until the damaged kidney undergoes spontaneous repair.@-i2 Recent studies13*14 have emphasized that urinary suppression and renal insufficiency of lower nephron nephrosis are self-limited disturbances and that the therapeutic value of such technics as the artificial kidney, peritoneal lavage, intestinal dialysis or exsanguination transfusion is therefore difficult to assess. This presentation of four cases of lower nephron nephrosis due to the inhalation of carbon tetrachloride is limited to a discussion of the occurrence, pathogenesis, prevention and treatment of associated congestive heart failure. It is designed primarily to emphasize that the deficient excretion of sodium and water due to primary renal disease can produce the complete syndrome of congestive heart failure without cardiac disease. In ordinary cases of heart failure the kidney may be regarded as the effector organ whose dysfunction is in part responsible for the clinical phenomena, but cardiac disease is the primary causative abnormality. In the cases of lower nephron nephrosis which are herein reported the clinical _ features of heart failure appeared in young and hitherto healthy individuals without past or present cardiac disease and could be attributed to the primary renal disease. Secondarily these cases are presented not only to re-emphasize the danger of fatal pulmonary edema due to overzealous administration of massive quantities of fluids but to stress the frequency of congestive heart failure with intakes of sodium and water which are not ordinarily excessive for individuals with normal hearts. The danger of fatal pulmonary edema due to massive intravenous infusions and the futility of such measures to overcome urinary suppression and progressive azotemia have become generally recognized. But there is still inadequate recognition of the frequency of edema and other evidences of congestive heart failure induced by the administration of moderate amounts of fluid which have no egress because of the complete or almost complete cessation of renal excretion of sodium and fluid. Finally this report is designed not merely to reiterate the self-limited nature of toxic nephrosis and the merits of conservative therapy but more particularly to stress that the treatment of carbon tetrachloride nephrosis should be directed chiefly toward the prevention and control of heart failure without regard to the concomitant azotemia and almost always without regard to the associated acidosis or electrolyte disturbances. Emphasis on the prevention and treatment of congestive heart failure is justified by the observation that fatalities * From The Mount Sinai Hospital, New York, N. Y.

On the Treatment of Uræmia with Intestinal Dialysis

On the Treatment of Uræmia with Intestinal Dialysis