Experimental approach to the correlation of hemodynamic changes with increases in urinary lactate dehydrogenase as a new parameter reflecting serious renal tissue damages.

From previous investigations with nephroptotic patients increased urinary LDH was assumed to be a reliable marker indicating a renal tissue defect due to the organs descent in erect position. Animal experiments now allowed correlation of this enzymatic activity with controlled changes of anatomical and physiological parameters. Changes of the renal hemodynamics or urinary flow induced in acute experiments in dogs simulated kidney displacement in nephroptotic patients. Both ureters were cannulated for separate urine collection and one kidney was manipulated. The renal arterial or venous flow was reduced or the ureter was occluded under electromagnetic blood-flow control. Arterial constriction alone (30%/15 min) selectively caused a drastic decrease (approximately 80%) of Xenon wash-out (= nutrient-flow) in the renal cortex. Under the same conditions radio-labeled microspheres injected intracardially showed a centralization of the renal capillary blood flow from the outer cortex to the juxtamedullary zone. Urinary LDH activities increased up to 800% immediately after arterial constriction. In accordance with total LDH activity the percentage distribution of isoenzymes changed: LDH-I increased and the LDH-V decreased. Neither constriction of the renal vein nor ureteral occlusion had similar effects. In long-term experiments backward fixation of one kidney in rats would reflect the effects of kidney displacement over years in nephroptotic patients: animals were unilaterally nephrectomized and the remaining kidney was dislocated backwards (approximately 2,5 vertebrae) and fixed to the lateral pelvic wall. "Ptotic" rats showed during the following examinations a constant increase of urinary LDH up to 50% by 26 weeks postoperatively. In accordance with increased LDH the isotope nephrogram was pathological and arteriographies showed a stretched and narrowed renal artery. In a number of rats "ptotic" fixation was not effective enough. All these animals showed normal LDH, isotope nephrograms and arteriographies. Both animal experiments documented that reduced flow/hypoxia is essentially responsible for the tissue damage in the kidney manifested by increased release of urinary LDH.

Diagnostic relevance of urinary lactate dehydrogenase determination in nephroptosis and for the indication to nephropexy.

Previously reported experiments with animals suggested that reduced renal arterial flow might be the actual cause for the pathogenicity of nephroptosis. Clinical studies now give evidence that measurements of urinary LDH may be a criterion equal to the isotope nephrogram (ING) in considering this disease. Patients with a "mobile" kidney verified by i.v. pyelography were examined by an ING and a 1-day test for urinary LDH. In accordance with periodic kidney displacement total urinary LDH activities were measured in a 8-h urine volume in the supine position and a 8-h urine volume in the erect position of the patients. Evaluations were all expressed as percentage increase of LDH activity of the patient in the erect versus supine position and correlated with his ING-pattern. Among 45 nephroptotic individuals 34 showed, in accordance with a pathological ING, a mean LDH increase of more than a 100%. Eleven individuals had normal INGs and less than 20% increase equal to a group of 16 normal controls. We postulated a 30% increase as the upper limit between normal and pathological urinary LDH. The percentage distribution of isoenzymes was also altered within the pathological LDH range: LDH-I, which increases in normal controls, now decreased in nephroptotic patients. LDH-IV and V, which decrease in controls, now increased. Homomeric isoenzymes obviously show reciprocal behavior. The degree of kidney descent in cm does not correlate with percentage increase of urinary LDH, i.e. it is not a criterion for pathogenicity. Biopsies taken during nephropexy revealed that from an anamnestic duration of 50 weeks onwards the kidney is significantly affected and tissue damages become evident. If patients were re-investigated after nephropexy they showed normal i.v. pyelograms and normal LDH and no longer had clinical symptoms.

Experimental evidence for a significant impairment of host defense for gram-negative organisms by a specific cutaneous toxin produced by severe burn injuries.

Dry heat forms a specific burn toxin in mouse and human skin from a naturally occurring precursor by a polymerization process and not by producing breakdown products. Precursor and toxin are both macromolecular lipid-protein complexes with similar chemical composition and physical structure both occurring in mouse and human skin as well as in serum of burned patients. Specific toxicity resides only in the apoprotein of the polymeric toxic form which also has new specific artificially produced antigenic site or sites. This phenomenon makes it possible to jump the species from man to mouse, shown by the success of specific immunotherapy. Neutral apolar lipids of the coat are contributing in an unspecific but significant manner to the toxic effect. Bacteria are not involved in toxin production nor in toxin activity. The target systems of the toxin are the cell wall membranes of all parenchymal cells of paractically all organs. The toxin apparently causes severe damage of the membrane verified by an increased permeability for compounds which otherwise do not penetrate. This basic cell damage itself is able to kill the animal, depending on the ratio of intact to damaged cells. Sublethal doses of toxin, however, prepare the background upon which bacteremia in burn injuries leads to a lethal sepsis. Finally, the direct toxic action as well as the enhancement of the susceptibility for gram-negative organisms both leading to the lethal outcome can be counteracted by specific passive antitoxic immunotherapy.

[Treatment of pseudomonas infection following burn injuries with specific antitoxic Ig-therapy]. / Die Beeinflussung der Pseudomonas-Infektion nach Verbrennungstrauma durch spezifische antitoxische Ig-Behandlung

The mortality rate of mice after standardized Pseudomonas infection was increased by preinjection of a sublethal dose of burn toxin. This effect was eliminated by a specific antitoxic Ig. After a sublethal burn followed by infection, 60% of the animals died, while treatment with specific Ig reduced the mortality rate to 3.3%. This might be a new way to improve the treatment of severely burned patients.

Burn sepsis and burn toxin.

The salient steps of a 20-year programme of research into the nature of burn disease are described. By burn disease we mean the late mortality and morbidity following burns. We have isolated a burn toxin which is derived from a thermal polymerization of cell membrane lipoproteins within the dermis and have studied its influence on the effects of sepsis. We have also used it in the development of active and passive immunization therapy of severe burns.