Regeneration following acute kidney damage

Acute renal failure was, and still is, a relative frequently observed disease (1% of the hospital population) with a bad prognosis (50% mortality). This prognosis remained unchanged over the last 40 years, on the one hand due to the changed, older patient population with his complex pathology, on the other hand the lack of efficient therapies capable to cure or prevent acute renal failure. Fortunately, the kidney, in contrast to some other organs, possess an important regeneration capacity after acute ischemic and/or toxic injury. This regeneration capacity manifests itself by a proliferation and migration of young cells along the denudated basal membrane of the injured segments within 24 hours after the acute insult. This proliferation is also seen at the interstitium and the non-injured distal tubule of the kidney. Some years ago intensive research was performed looking for possible renal growth factors, being the initiators of this important proliferation. Indeed, the kidney expresses several growth factors such as 'epidermal growth factor', 'insuling growth factor', 'platelet growth factor', 'hepatocyte growth factor', 'transforming growth factor alpha', and 'transforming growth factor beta'. However, studies performed in several models of acute renal injury observed an almost complete disappearance of these growth factors immediately after the insult, measurement at the level of mRNA and protein. On the other hand, the receptor-density for some growth factors at the level of the baso-lateral site of the cells of the injured segments is upregulated. The kidney itself is not the source of growth factors, she is eager to take up a number of growth factors, a possible mechanism for the repairing proliferation. Based on these findings and the fact that a clear cellular infiltrate goes along with each acute renal insult, the question was raised if there is a role for this cellular infiltration in the regeneration process? We and others could demonstrate that soon after the insult a fast interstitial infiltration/proliferation occurs and that this cellular infiltration is mainly surrounding the injured segments of the nephron. This infiltration does not consists of neutrophils but of macrophages and T-cells. Even in the case of an ischemic insult, in contrast to the current literature, the cellular infiltration does not contain neutrophils. We found that the contribution of the neutrophils is negligible compared to the macrophages and T-cells. An explanation could be found in the fact that the methods, used to identify the neutrophils, are not specific for this particular leukocyte subset. Several experiments were performed searching for a role of the cellular infiltrate using athymic rats (absence of T-cells), knock-out mice (ICAM1 or iNOS deficient) performing leukocyte depletion experiments with appropriate antibodies; applying antisense oligonucleotides (ICAM1), all point towards the same direction: prevention of the formation of an interstitial infiltrate results in almost no decrease of renal function after acute injury. This favourable effect on renal function does not preclude a role of this interstitial infiltrate in the regeneration process of the damaged nephron segments. Further research will have to show if the infiltrate can not be the source of the growth factor, initiating the important renal proliferation/regeneration. It is clear that this infiltrate has to disappear, a process in which apoptosis plays a central role. Indeed, it was shown that a maintained macrophage T-cell infiltrate can provoke interstitial fibrosis and finally chronic renal failure.     

The phenomenon of resistance to a thiazide diuretic in acute kidney failure

The resistance to hypothiazid (hydrochlorothiazide) during the development of acute renal insufficiency (ARI) induced by glycerin injection was studied in rat experiments. Natriuretic, kaliuretic, and hydrouretic activity of the diuretic decreased two days after injection of a glycerin solution. In this period hypothiazid excretion with the urine was least. Ten days later, despite the restoration of the water- and electrolyte-excretion function of the kidneys and normalization of hypothiazid excretion with the urine, the natriuretic effect of the drug was still very poor. This is indirect evidence of the long-term affection of the receptors for the thiazid diuretics during the development of ARI. The affection remains even after the excretory function of the kidneys is restored. The high correlation between the cumulative excretion of hypothiazid with the urine and natriuresis encountered in intact animals was weaker in rats with acute renal insufficiency.     

Changes in intracellular and extracellular calcium concentration of the myocardial cells during heart failure in children

OBJECTIVE: To explore the relationship between heart failure and changes in intracellular calcium concentration of the myocardium. METHODS: The intra-and extracellular concentration of ionized calcium and total calcium of myocardium in 11 cases of heart failure was measured using calcium fluorescence indicator Fura-2 and atom absorption spectrophotometry. The activity of the erythrocyte membrane pump was determined with hemolysate chemical method. RESULTS: The concentration of ionized calcium in myocardial cells and the erythrocyte was significantly higher in the patients with heart failure (280.85 +/- 47.8 nmol/L, 1.76 +/- 0.04 F335/F385) than in those without heart failure (121.88 +/- 13.15 nmol/L, 1.47 +/- 0.08 F335/F385). Total calcium in the erythrocyte was also increased markedly in the patients with heart failure, but the activity of the erythrocyte membrane pump was lower than in those without heart failure. The intracellular calcium of the peripheral erythrocyte and the activity of membrane pump returned to normal after the heart failure was cured. CONCLUSION: There is excessive calcium accumulation in the myocardium and erythrocyte and the latter may be cause of the disturbance of myocardial diastolic function during heart failure.     

Renal blood flow velocity in acute renal failure following cardiopulmonary bypass surgery

Two lysosomal storage diseases, aspartylglucosaminuria and mannosidosis, are associated with highly elevated serum dolichol concentrations. To elucidate possible mechanisms leading to elevated serum dolichols, we studied the effects of Triton WR 1339 (known to increase serum cholesterol) and orotic acid (known to decrease serum cholesterol) on blood and biliary dolichol and beta-hexosaminidase levels in rats. In Triton WR 1339-treated rats, serum dolichol was markedly increased compared with saline-treated controls 1 (400 +/- 70 ng/mL, n = 7 v 85 +/- 11 ng/mL, n = 8, P < .001), 4 (789 +/- 70 ng/mL, n = 10 v 110 +/- 10 ng/mL, n = 7, P < .0001), and 8 (549 +/- 43 ng/mL, n = 8 v 87 +/- 8 ng/mL, n = 7, P < .001) days after administration of the drug. By contrast, serum dolichol was decreased (64 +/- 5 ng/mL, n = 8 v 119 +/- 7 ng/mL, n = 8, P < .0001) after a 7-day orotic acid feeding compared with controls. Serum beta-hexosaminidase was unaffected by both treatments. Orotic acid also increased biliary dolichol (280 +/- 47 ng/100 g body weight [BW]/h, n = 7 v 83 +/- 15 ng/100 g BW/h, n = 7, P < .01) and beta-hexosaminidase (21 +/- 3 mU/100 g BW/h, n = 7 v 8.3 +/- 2 mU/100 g BW/h, n = 9, P < .01) excretion compared with controls. Thus, both Triton WR 1339 and orotic acid have an effect on dolichol metabolism, and it is conceivable--based on our results--that serum dolichol concentrations are regulated, at least in part, by a mechanism similar to that for serum cholesterol levels.     

Low CSF concentration of a dopamine metabolite in tobacco smokers

We developed a monoclonal antibody-based, antigen capture sandwich enzyme-linked immunosorbent assay (ELISA) for bovine coronavirus. We compared the ELISA with electron microscopy and the hemagglutination test and found a close correlation between them. The sensitivity of the ELISA was 10(4) bovine coronavirus particles per ml of 10% fecal suspension. Compared with electron microscopy, bovine coronavirus ELISA had 96% specificity.     

Acute kidney failure in hypothermia

Two cases with acute renal failure after prolonged hypothermia are presented. Both patients were found in come, became rapidly uremic and required hemodilaysis treatment. Although the laboratory findings were typical of severe muscle damage, e.g. elevated levels of serum creatinine phosphokinase, serum lactic dehydrogenase and serum aldolase activities, visible "crush-injuries" were not found. Acute renal failure was characterized by extreme catabolism and severe metabolic acidosis. After 4 and 10 hemodialyses respectively, the patients became polyuric and finally were discharges with normal renal and muscle function. Hypotension with diminished renal perfusion and nontraumatic rhabdomyolysis due to prolonged hypothermia are regarded as the dominant pathogenetic factors in the acute renal failure.     

Changes in the brain monoamine metabolism in acute liver failure produced by ischemia-reperfusion injury in rats

Ninety-five patients with 107 trigger digits were divided into 2 groups and studied prospectively to evaluate steroid injection placement and efficacy. In 1 group, an attempt was made to deliver 1 injection into the tendon sheath at the A1 pulley. In the other group, 1 injection infiltrated the subcutaneous tissues overlying the A1 pulley. Radiopaque dye provided contrast to the injection medium, and postinjection x-rays identified the true delivery site of the steroid solution. Of the 52 digits into which intrasheath injection was attempted, 19 digits (37%) received all the injection within the sheath, 24 (46%) received medication into both the sheath and the subcutaneous tissues, and 9 (17%) received no medication within the tendon sheath. The results were analyzed to determine whether injection placement influences the efficacy of steroid injection. The confirmed all-sheath injection group exhibited a 47% good response, the mixed sheath and subcutaneous group had a 50% good response, and the all-subcutaneous group had a 70% good response. The results of this study suggest that true intrasheath injection offers no apparent advantage over subcutaneous injection in the treatment of trigger digits.