This investigation studies the toxicity of heme proteins and/or their break-down products on renal function. Heme proteinemia precedes acute tubule necrosis at a frequency great enough to suggest a causal relationship between the two events. Physiological and metabolic functions of kidney slices are investigated in several models of acute tubule necrosis. Organic acid and organic base transport is depressed earliest. These alterations in tubule function cannot be explained by ischemia or obstruction alone. Heme proteinemia in rats or incubation of renal slices in medium containing heme proteins yields several interesting observations. Neither in vivo or in vitro do hemoglobin and methemoglobin alone produce a depressive effect on the transport systems studied. However, parallel to many clinical situations, when such secondary insults as hypoxia and elevated ammonia concentrations are included in the experimental design, transport functions are depressed. Ferrihemate, a molecule smaller than hemoglobin or methemoglobin, depresses transport function without secondary insults. From these studies it is concluded that heme proteins play a role in tubule dysfunction seen in acute tubule necrosis. A model is presented that collates these data with other factors known to play a part in the pathogenesis of this renal syndrome.

1. While azotaemic sera depressed the in-vitro Na-iodohippurate transport of rat kidney slices at any concentration, normal sera excited transport at low concentrations and depressed transport at high concentrations. The depression of transport by azotaemic sera was partially overcome by neomycin feeding in contrast to the depression by normal sera, which was not altered by neomycin feeding.2. Plotting the reciprocal of sodium-iodohippurate accumulated by slices against the reciprocal of the media concentrations of sodium iodohippurate suggested that the depression of hippurate transport produced by normal and azotaemic sera was competitive in nature.3. Normal sera slowed the efflux of Na-iodohippurate from kidney slices while azotaemic sera affected it very little.4. The depression produced by normal and azotaemic sera and the stimulation produced by low concentrations of normal sera were seen with serum ultrafiltrates and dialysates, and after passage through cation exchange columns, but not anion exchange columns.5. The effects on Na-iodohippurate accumulation by normal and azotaemic sera could be reproduced with metabolizable (lactate), and nonmetabolizable (hippurate) organic anions as well as combinations of these.6. The implications of these observations on the altered renal transport of Naiodohippurate produced by azotaemic and normal sera are discussed.Azotaemic sera contain dialysable substances that depress organic anion transport as represented by hippurate or para aminohippurate accumulation (Preuss, Massry, Maher, Gilliece

1. The effects were investigated of non-dialysable substances obtained from urines of patients with nephrotic syndrome and those with myelomatosis (heavily laden with light chains) on renal function in a system in vitro. 2. The ability of the rat kidney slice to accumulate hippurate and tetraethylammonium (TEA), and to produce ammonia and glucose, was measured after incubation in urine proteins from ten patients with myelomatosis. All slice functions measured at protein concentrations of 10 mg/ml decreased significantly compared with control. Hippurate accumulation averaged 58%, TEA accumulation, 53%, ammoniagenesis, 59%, and gluconeogenesis, 57% of control. An inverse relationship between protein concentration and hippurate accumulation was noted. 3. Slices incubated in proteins from eight nephrotic patients showed no consistent decrease from control in hippurate accumulation (95%), TEA accumulation (103%), ammoniagenesis (91%) or gluconeogenesis (92%). 4. Since urinary proteins from patients with myelomatosis, unlike urinary proteins from the nephrotic patients, had a consistently deleterious effect on the function of renal slices, this suggests that proteins found in urines from myelomatous patients may play a role in the disturbance of proximal tubular function sometimes seen in this disorder.