Fibrin breakdown products and fibrinolysis in renal disease.

In chronic renal failure and after acute renal failure, fibrinogen levels are raised and there is diminished fibrinolysis as the result of renal damage. A similar situation is found in nephrosis, possibly due to fibrinolytic inhibitors. Increased levels of cryofibrinogen were found in one quarter of cases of acute nephritis, nephrosis, and acute and chronic renal failure. In addition, after acute renal failure low platelet counts, prolonged thrombin times, and high levels of fibrin degradation products, yet with diminished fibrinolysis, indicate that intravascular coagulation has occurred. A positive result for fibrin degradation products was found in 17 of 20 cases of acute renal failure but in none of 10 cases of chronic uraemia. Intravascular coagulation is a process in which fibrin is deposited in the glomerular filters and may account for anuria, and, in the renal vasculature, where it may cause ischaemic tubular necrosis.

Studies of contact activation of blood in haemodialysis.

A study of patients on Kiil and Travenol coil dialysis has shown that kallikrein esterase, the kinin precursor, is increased in the venous blood during dialysis and that this is accompanied by an increase in the venous effluent of the dialysers. In addition Hageman factor depletion and an increase of platelet factor 4 has been found in the venous effluent. Such studies indicate surface activation of coagulation in the dialysers and will be of use in future studies of the suitability of different dialysers.

Circulating lysosomal enzymes and acute hepatic necrosis.

The activities of the lysosomal enzymes acid and neutral protease, N-acetylglucosaminidase, and acid phosphatase were measured in the serum of patients with fulminant hepatic failure. Acid protease (cathepsin D) activity was increased about tenfold in patients who died and nearly fourfold in those who survived fulminant hepatic failure after paracetamol overdose, whereas activities were increased equally in patients with fulminant hepatic failure due to viral hepatitis whether or not they survived. A correlation was found between serum acid protease activity and prothrombin time, and the increase in cathepsin D activity was sustained over several days compared with aspartate aminotransferase, which showed a sharp early peak and then a fall. Circulating lysosomal proteases can damage other organs, and measurement of their activity may therefore be of added value in assessing prognosis in this condition.

Proteins and fibrinolysis in recipients of renal allografts.

Studies of serum proteins, platelets, and fibrinolysis in patients after renal allografting show that a fall in plasma fibrinogen in the postoperative period can be associated with early rejection and that a rise in serum fibrin degradation products when accompanied by a fall in platelets is associated with rejection. Fibrinolysis is depressed in these patients until two months after transplantation and marked depression of fibrinolysis may precede rejection. The late coincidence of fibrinolytic depression with a rise in fibrin degradation products suggests chronic insidious rejection.

How toxic are phenols?

How toxic are phenols? The phenolic acids cannot all be detoxified. Phenyl-glucuronide, although water soluble, can still disturb cell membrane transport mechanisms. Apprecialbe amounts of toxic-free phenols form a lipid pool in the uremic patient. These findings are also relevant to hepatic coma.

How does hyperglycaemia predispose to diabetic nephropathy?

Diabetic nephropathy is preceded by 'hyperfiltration' mediated by dilatation of the afferent arterioles to the glomeruli by means of IGF-1, prostaglandins, bradykinin, nitric oxide and atrial natriuretic peptide, together with constriction of the efferent arterioles by local thromboxane A2. Raised glomerular intracapillary pressures might then contribute to glomerulosclerosis, but in any case there is permeability of the vascular endothelium. AGEPs and lipid peroxides can explain this. AGEPs, or simply intermittently high levels of glucose, also account for synthesis of extracellular matrix proteins that lead to thickening of the basement membrane and glomerulosclerosis. Another glucose product, glucosamine-6-phosphate, is formed when there is hexosamine flux along with insulin resistance in tissues, and is implicated in glomerulosclerosis, since it also stimulates TGF-beta transcription. In seeking to explain proteinuria, depletion of heparan sulphates from the endothelial cells and GBM is now established as a principal cause. In addition to a high glucose reducing the synthesis of heparan sulphates, it has now been shown that high glucose may depress the synthesis of heparin sulphate proteoglycan.

Vascular permeability in diabetics and implications for therapy.

Several factors contribute to increased vascular permeability in diabetes mellitus, namely hyperglycaemia leading to increased production of diacylglycerol and thence protein kinase C, non-enzymatic glucosylation generating free radicals and lipid peroxides, sorbitol formation, loss of endothelial cell surface heparan sulphates, and the action of arachidonate derivatives that affect endothelial cell contractility. In view of the importance of oxidative damage, serious consideration must be given to therapeutic regimens that utilise vitamin E or ascorbic acid or D-myoinositol. Probucol is an available antioxidant whose properties have received insufficient attention. The oleate of monounsaturated oil diets is likewise anti-oxidant. Furthermore there is a possibility of replacing lost surface heparan sulphates.

Low-molecular-weight (tubular) proteinuria is not related to glycaemic control in non-insulin dependent diabetes mellitus.

Early morning urine specimens were obtained from two groups of non-insulin dependent diabetic patients and a group (43 subjects) of normal controls. The diabetic patients were divided into two subgroups according to the degree of diabetic control as judged by their glycosylated haemoglobin (HbA1) levels (well-controlled, 47 subjects; poorly controlled, 51 subjects). The concentration of the low-molecular-weight enzyme (lysozyme) was determined in each urine specimen and related to the concentration of creatinine (lysozyme/creatinine). The mean urinary lysozyme concentration was higher in each of the two diabetic groups as compared with the control group. However, it was not significantly different between the two diabetic groups. These result suggest that there is no association between the degree of glycaemic control and tubular proteinuria.

Endotoxinemia in renal transplant recipients.

Endotoxinemia in renal transplant recipients. In immunosuppressed renal transplant recipients a high incidence of endotoxinemia was found during chest or urinary tract infections. Although the endotoxinemia was protracted, indicating inability to eradicate the infection, yet in general the effects were benign and adverse renal damage was not seen. The Limulus gelation test has a positive contribution to make in the diagnosis of illness in transplant recipients.

Free phenols in chronic renal failure.

Serum total free phenols are elevated in chronic renal failure, acute renal failure and hepatic coma. Being partly protein-bound, phenols behave during dialysis in a similar manner to considerably larger molecules which are not protein-bound. In view of their potential toxicity they should be considered as an alternative to 'middle molecules'. Patients on regular hemodialysis have retention of phenols if their post-dialysis serum creatinine is above 6-7 mg/dl. Patients on short time dialysis have high pre-dialysis neutral phenol levels. Such levels are sufficiently high to suggest a role in the genesis of neurological symptoms, anemia and bone disease. Certainly pre-dialysis free phenols reflect adequacy of dialysis.

Serum proteins as indicators of poor dietary intake in patients with chronic renal failure.

A study of serum proteins in patients on regular hemodialysis has shown that many have low serum transferrin levels but near normal serum albumin and normal or raised pre-albumin levels. Hemoglobin values were related to transferrin levels. Low transferrin levels also occurred in patients with advanced osteitis fibrosa. Deficient protein intake seems the likely explanation. Measurement of pre-albumin does not reflect low protein intake in chronic renal failure; reasons for this discussed.

Altering the course of proliferative nephritides: the challenge of the 1990s.

There is considerable evidence based on experimental pathology that heparin/heparinoids will benefit the course of the various forms of human proliferative nephritis. An alternative to heparin may be pentosan polysulphate. Another possibility is the infusion of prostaglandin E1 because of its anti-inflammatory and potentially antiproliferative actions. Both these approaches mimic natural pathophysiological control mechanisms.

The functional role of intravascular coagulation renal disease.

There is evidence of intravascular coagulation in accelerated hypertension and pre-eclamptic toxaemia, in all types of nephritis and in the haemolyticuraemia syndrome. The kidneys have a two-fold defence mechanism, namely mesangial cell phagocytosis and endothelial cell fibrinolytic activity. Intravascular coagulation occurs in all those types of shock that result in acute renal failure: more often than not the primary cause is endotoxinaemia.