Fibrinolytic activators and inhibitors in terminal renal insufficiency and in anephric patients.

Fibrinolytic factors were measured before and after DDAVP-infusion in 18 patients on chronic, regular haemodialysis, 11 of whom underwent bilateral nephrectomy, and in 7 patients in whom non-functioning kidneys were still present. Baseline fibrinolytic activity was normal or high in all but two cases. Before haemodialysis, the response to DDAVP-infusion was greatly reduced in the majority of patients as compared with healthy controls, irrespective of the baseline level. This was in accordance with mean t-PA-antigen levels which increased only slightly after DDAVP. When DDAVP was given after haemodialysis, previous non-responders showed a normal increase in fibrinolytic activity. The level of free t-PA-inhibitors was normal in most cases as were levels of alpha 2-antiplasmin and alpha 2-macroglobulin.

Large-pore hemodialytic procedures in pigs with ischemic hepatic necrosis; a randomized study.

In order to define further the therapeutic role of hemodialytic procedures in acute hepatic failure, 20 pigs with ischemic hepatic necrosis underwent randomized hemodialysis against an electrolyte solution (n = 6), hemofiltration with re-infusion of an electrolyte solution (n = 5), control hemofiltration with re-infusion of autologous ultrafiltrate (n = 4) or no extracorporeal procedure at all (n = 5). Pigs on hemodialytic procedures survived significantly longer (51 +/- 11 hrs) than controls (36 +/- 8 hrs). There were no differences in the duration of survival between hemodialysis and hemofiltration, nor between controls undergoing and those not undergoing an extracorporeal procedure. Electroencephalograms showed more rapid (p less than 0.05) deterioration in control animals than in the treatment group. Putative toxins such as ammonia, glutamine, tyrosine, tryptophan, and methionine all decreased transiently in the treatment group; in the control group a continuous increase in the levels of the putative toxins was observed. Comparison of all pigs surviving 35 hrs or less (n = 6) and animals surviving more than 45 hrs (n = 7) showed that long-term survival was significantly associated with lower plasma ammonia and methionine concentrations and fewer abnormalities on the electroencephalogram 10 hrs after the start of extracorporeal procedures; moreover six of the 7 long-term survivors underwent hemodialysis or hemofiltration procedures. We conclude that hemodialytic procedures prolong survival in pigs with ischemic hepatic necrosis by slowing the development of encephalopathy; this effect of hemodialytic procedures may be mediated by the lowering of plasma ammonia and methionine levels.

The immunochemical determination of apolipoprotein A, total apolipoprotein A-I and 'free' apolipoprotein A-I in serum of patients on chronic haemodialysis.

We have determined by radial immunodiffusion the apolipoprotein A content of undelipidated serum samples from 30 patients on chronic haemodialysis and 28 controls using an antiserum against high density lipoprotein (anti-apolipoprotein A). We found that the patients had lower concentrations of apolipoprotein A than the controls. When an antiserum against apolipoprotein A-I was used and the samples were delipidated prior to radial immunodiffusion there was, however, no difference in the total amount of apolipoprotein A-I between the two groups. We were able to explain this difference by measuring the amount of 'free' apolipoprotein A-I after crossed immunoelectrophoresis of undelipidated samples, using the antiserum against apolipoprotein A-I. We found that the patients had a higher level of 'free' apolipoprotein A-I than the control group. Since apolipoprotein A-I inhibits hepatic triglyceride lipase, the increase in triglycerides observed in patients on haemodialysis may be caused by the greater concentration of 'free' apolipoprotein A-I in their serum.

Observations on computerized quantitative bone scintigraphy in renal osteodystrophy.

Skeletal radiotracer (99mTc-HEDP) uptake was quantitated with and without the aid of a computer in 30 chronic dialysis patients with histologic evidence of renal osteodystrophy. Before scintigraphy, elevated soft-tissue activity due to the absence of renal radiotracer excretion was reduced by hemodialysis. The results were compared with those of a normal group and with the results of the biochemical and the bone morphometric studies of these patients. In all patients the radiotracer uptake was elevated, often markedly. In several patients with minimal histologic bone disease, however, soft-tissue activity could not be normalized by hemodialysis although its influence on the quantitative data could be further reduced (but not excluded) by computer evaluation of skeletal radiotracer uptake. Since the latter technique clearly distinguished the majority of the patients from the normals, it appears that computerized quantitative skeletal analysis is a potentially accurate scintigraphic method for detecting renal osteodystrophy. The significant relationship between skeletal radiotracer uptake, in particular at the bone biopsy site, and only the histologic features of increased bone turnover suggest that hyperparathyroidism is the major cause of this increased tracer uptake in renal osteodystrophy.

Incidence of endotoxemia in pigs with ischemic hepatic necrosis treated by hemodialysis. Prevention of endotoxemia with lactulose.

The incidences of endotoxemia and bacteremia were evaluated in 30 pigs with ischemic hepatic necrosis treated by hemodialytic procedures. Prior to induction of hepatic ischemia, ten pigs underwent bowel cleansing by means of an oral dose of magnesium sulfate, and 20 received a combination of magnesium sulfate and lactulose. Endotoxemia and bacteremia seldom occurred during the development of hepatic encephalopathy, but the incidence of both increased markedly shortly before death. Pigs pretreated with magnesium sulfate and lactulose however did not develop preterminal endotoxemia. A significant relation between endotoxemia or bacteremia and survival was not found, irrespective of pretreatment with lactulose. Of the positive limulus tests, 67% were accompanied by a positive blood culture, while 42% of all positive blood cultures were associated with a positive limulus test. Dialysis with dialysates contaminated with endotoxins did not increase the risk of endotoxemia. It is concluded that in an animal model of ischemic hepatic necrosis (1) endotoxemia and bacteremia appear mainly in the preterminal stage, but do not influence the duration of survival significantly; (2) lactulose prevents endotoxemia and (3) dialytic procedures do not increase the risk of endotoxemia and bacteremia.

Comparison of large-pore membrane haemodialysis and cross-dialysis in acute hepatic insufficiency in pigs.

We studied the duration of survival and the removal of putative toxins in forty pigs with ischaemic hepatic necrosis, undergoing haemodialysis or cross-dialysis with a large-pore membrane. Ischaemic hepatic necrosis was induced in conscious animals by tightening a loop around the hepatic artery 3 days after construction of a portocaval shunt. Pigs treated by a dialysis procedure survived significantly longer (45.2 +/- 11.9 h) than controls (26.3 +/- 5.4 h). There was no difference between haemodialysis and cross-dialysis. Blood ammonia initially dropped significantly (P less than 0.05) more during haemodialysis (560 +/- 107 leads to 210 +/- 51 mumol/l) than during cross-dialysis (596 +/- 131 leads to 398 +/- 81 mumol/l) but it subsequently increased beyond initial values despite efficient removal during continuous dialysis. Removal of ammonia was greater during cross-dialysis than during haemodialysis, but haemodialysis was more effective in the removal of the ammonia precursors glutamine and urea. We conclude that dialysis procedures can prolong survival in pigs with ischaemic hepatic necrosis. The removal of ammonia-precursors is more effective in the prevention of hyperammonaemia than the removal of ammonia itself. Since dialysis cannot prevent progressive hyperammonaemia, control of excessive toxin production seems mandatory for effective hepatic support.

The use of desmopressin acetate (DDAVP) as a test of the fibrinolytic capacity of patients--analysis of responders and non-responders.

Intravenous infusion of desmopressin (DDAVP, 0.4 micrograms/kg b.w. in 12') causes an increase in the level of extrinsic plasminogen activator, measured in plasma euglobulin fractions with added C1-inactivator on fibrin plates. A poor response or no response at all was elicited in two out of 21 patients with spontaneous thrombosis, 18/38 with hyperlipoproteinaemia and 10/14 with terminal renal insufficiency requiring haemodialysis. Haemodilution during the first 30' after starting the DDAVP-infusion occurred both in responders and in non-responders; so did haemodynamic reactions: increase in heart rate, drop in diastolic blood pressure, facial flushing. The rise of fibrinolytic activity was shown not to be associated with decreased hepatic blood flow. Normal factor VIII-rises in "non-responders" indicate the responsiveness of the receptive organs, including the hypothalamus, to DDAVP. Despite a normal baseline level of fibrinolytic activity in the blood, as occurs for instance in terminal renal insufficiency, the vascular endothelium may be refractory to stimulation. In some patients especially in type IV hyperlipoproteinaemia, a selective defect of the release of plasminogen activator is postulated. In subjects with low fibrinolytic activity at rest, as observed in spontaneous thromboembolism and in hypertriglyceridaemia, the failure to release plasminogen activator upon stimulation with DDAVP might be a consequence of an impairment of synthesis as well.

Increased bone radiotracer uptake in renal osteodystrophy. Clinical evidence of hyperparathyroidism as the major cause.

Bone radiotracer uptake in renal osteodystrophy was investigated in 35 dialysis patients by correlating the results of quantitative bone scintigraphy with those of biochemical and bone morphometric studies. There were highly significant correlations (P less than 0.001) between the total skeletal activity and the biochemical (iPTH and alkaline phosphatase), and histologic parameters of hyperparathyroidism. These clinical results strongly suggest that increased bone turnover i.e. hyperparathyroidism, rather than osteomalacia is the major cause of increased skeletal uptake in renal osteodystrophy.

Effects of an angiotensin-converting enzyme inhibitor (captopril) on blood pressure in anephric subjects.

Randomised, double-blind cross-over trials were performed in seven anephric patients to determine the effect of the orally active angiotensin-converting enzyme inhibitor captopril on blood pressure in fluid-depleted and fluid-replete patients. Patients were given captopril, 100 mg orally, or placebo one hour after haemodialysis, when they were fluid depleted. Their mean (+/- SEM) supine blood pressure fell from 127 +/- 12/71 +/- 6 mm Hg before captopril to 106 +/- 13/54 +/- 4 mm Hg 24 hours after the drug, while on placebo it rose from 123 +/- 11/73 +/- 5 mm Hg to 134 +/- 10/82 +/- 8 mm Hg. All patients developed orthostatic hypotension after captopril. In the fluid-replete state, two days after haemodialysis, captopril had no effect on blood pressure. The plasma concentration of active renin was extremely low and did not rise after fluid withdrawal or captopril. Thus the hypotensive effect of captopril did not appear to depend on circulating renin concentrations. The concept of "renin-dependent" hypertension, which is responsive to captopril, as opposed to "volume-dependent" hypertension, which is not responsive to captopril, may therefore be invalid.

Metastatic skin calcification. A rare phenomenon in dialysis patients.

Calcification of the skin could not be demonstrated in 60 skin biopsy specimens, selectively obtained from 30 chronic hemodialysis patients; 21 of these patients had metastatic calcification at other sites. These results support the proposed rarity of metastatic skin calcification in patients with chronic renal failure. The cause of this phenomenon is not precisely known.

Scintigraphic detection of gastric calcification in dialysis patients.

The value of 99mTc HEDP bone scintigraphy as a means of detecting metastatic gastric calcification was studied in 45 chronic dialysis patients and in 55 former dialysis patients. For this group, all bone scans were obtained within 2 months after successful transplantation; radiotracer uptake by the stomach was not observed. In 15 of the first 35 chronic dialysis patients studied, gastric uptake was demonstrated without radioactive accumulation in the thyroid region. In all the dialysis patients, however, background activity had been normalized before scintigraphy by means of hemodialysis using recirculating dialysate. Without the latter, radioactive accumulation in the stomach was no longer noted. Thus, gastric uptake was presumably due to the formation of in vivo free pertechnetate, as a result of the dialysis method used, and in vitro experiments supported this hypothesis. These findings show that free pertechnetate can cause visualization of the stomach in the absence of thyroid imaging. The results of this study further indicate that bone scintigraphy is not a sensitive method for detecting metastatic gastric calcification in uremia.

Bone scintigraphy in uremic pulmonary calcification.

The value of Tc-99m HEDP bone scintigraphy as a means of detecting uremic pulmonary calcification was studied in 30 chronic dialysis patients. A high incidence of currently recognized predisposing factors for metastatic calcification was found and calcification was recorded at other sites. Scintigraphy was performed after reducing background activity by hemodialysis to levels found in normals. From chest images and chest-to-spine activity ratios, evidence of pulmonary calcification could be obtained in only one patient, and subsequent histologic examination revealed extensive calcification. High chest-to-spine activity ratios suggested increased pulmonary radionuclide uptake in several other patients, but these findings were not conclusive. These results indicate that uremic pulmonary calcification--which, according to autopsy studies, develops in about 60-75% of dialysis patients--cannot be detected with bone-seeking radiopharmaceuticals, unless the calcification is severe. This is probably due to the unusual crystalline and chemical composition of uremic pulmonary calcification.

Bone scintigraphy in renal osteodystrophy.

Bone scintigraphy with Tc-99m HEDP was performed in 30 patients on maintenance hemodialysis, and the results of quantitative analysis were compared with those of a normal group. To permit this comparison, elevated background activity due to the absence of renal radiotracer excretion was reduced by hemodialysis to levels found in the normals. Histologic proof of renal osteodystrophy had been obtained in all patients. The incidence of radiographic abnormalities was 46%, whereas abnormal scans were found in 25 patients (83%); skeletal lesions were also more pronounced and detected earlier. However, even when the scans appeared normal, the quantitative analysis showed increased skeletal activity in all patients. The total skeletal activity proved to be a good index of the severity of renal osteodystrophy and appeared dependent on both osteomalacia and hyperparathyroidism. These findings show that bone scintigraphy is a sensitive method to detect skeletal involvement in renal osteodystrophy.