Burton D. Cohen

Further studies on the platelet-inhibitory effect of guanidinosuccinic acid and its role in uremic bleeding

The average guanidinosuccinic acid (GSA) level in the serum of seventeen uremic subjects was found to be 2.53 mg per cent (0.15 mM) with a range of 0.86 to 5.4 mg per cent; serum GSA was less than 0.15 mg per cent in each of seventeen normal subjects. Measured GSA levels are sufficient to account for the inhibition of adenosine diphosphate (ADP)-induced platelet factor 3 (PF-3) activation, which we have previously demonstrated in citrated uremic plasma. GSA levels and the degree of inhibitio of ADP-induced PF-3 activation decreased in parallel in the serum and plasma of uremic patients undergoing peritoneal dialysis. In vitro inhibition of ADP-induced PF-3 activation did not occur with urea, creatinine, guanidinoacetic acid or arginine. GSA inhibited the second wave of platelet aggregation induced by ADP or by epinephrine and reduced the degree of aggregation induced by collagen suspensions. At increased concentrations of ADP and l-epinephrine the second wave of aggregation (attributed to release of endogenous platelet ADP) was again demonstrated. The aggregation of uremic citrated platelet-rich plasma (C-PRP) required nearly twice as much ADP as did normal C-PRP for either the second wave of aggregation or a maximal aggregation response. Acetyl salicylic acid (ASA) at equimolar concentrations was as effective as GSA in inhibiting both ADP-induced PF-3 activation and platelet aggregation, but the two inhibitors differed in several respects. Exposure to GSA makes the dense tubular system of normal platelets more prominent and inhibits the internal transformation characteristic of their response to ADP; these ultrastructural changes correlate with the inhibition of the second wave of aggregation. Thus, GSA at levels found in the serum of uremic patients can account for a number of the in vitro abnormalities of uremic platelet function and may be partly responsible for the bleeding syndrome of uremia.

Guanidinosuccinic acid in renal failure, experimental azotemia and inborn errors of the urea cycle.

Abstract An Improved method of isolation and quantitation, using Dowex-1 ion-exchange chromatography and paper electrophoresis, has permitted efficient recovery of guanidinosuccinic acid from serum, urine and cerebrospinal fluid. Mean concentration of this acid in normal urine is 1.71 ± 1.60 (SD) mg/100 ml, and 5.35 ± 2.68 mg/100 ml in urine from uremic patients. Serum and cerebrospinal-fluid levels are also increased in uremia. In patients undergoing peritoneal dialysis, guanidinosuccinic acid was dialyzable. The metabolic pathway for synthesis of guanidinosuccinic acid is unknown. The increased excretion of this compound in rats treated with arginine, coupled with the failure to demonstrate the metabolite in the urine of patients suspected of having arginine deficiency resulting from genetic defects of the urea cycle, suggests that arginine is an intermediate in guanidinosuccinic acid synthesis.

Severe Acidosis and Hyperpotassemia Treated with Sodium Bicarbonate Infusion

Four uremic patients with severe acidosis, hyperpotassemia, and electrocardiographic signs of toxicity were treated with intravenous sodium bicarbonate. Serial determinations showed a fall in plasma potassium, a rise in blood pH, and regression of the electrocardiogram toward normal. The mechanisms responsible for these changes are discussed.

Use of a Calcium Chelating Agent(NaEDTA) in Cardiac Arrhythmias

The interrelated effects of digitalis and various cations on cardiac rhythmicity are the subject of much recent interest. This paper presents additional data on this subject that carry important therapeutic implications. The chelating agent, disodium ethylene diamine tetra acetate (NaEDTA), has been used intravenously in 14 instances of supraventricular and ventricular arrhythmia. Digitalis had been administered previously in 13 instances, and various degrees of digitalization were encountered. This report summarizes our experience with NaEDTA as a test of the degree of digitalis therapy and as treatment of the arrhythmias observed.

Severe metabolic alkalosis with neurologic abnormalities; report of a case.

EXTREME degrees of hypokalemic and hypochloremic alkalosis are occasionally seen in the adult patient. The case reported below is an example of such a metabolic abnormality, the severity of which i...

Tietze's disease of eight years' duration.

IN 1921 Tietze1 described 4 cases of a painful, nonsuppurative swelling of one or more costal cartilages associated with local tenderness that regressed spontaneously. Kayser,2 in 1956, reviewed th...

Electrocardiographic interrelationship of the pre-excitation (Wolff-Parkinson-White) syndrome and myocardial infarction

Abstract A case is presented in which electrocardiographic evidence of myocardal infarction is demonstrated in a patient with intermittent pre-excitation (Wolff-Parkinson-White) syndrome. It has been shown in this case that the QRS complex of pre-excitation phenomenon can both simulate and mask that of myocardial infarction, and that J-T segment alterations can be due to either or both when these two conditions co-exist.

Refractory edema treated with calcium chloride in combination with mercurial diuretics

Abstract Data are presented on 12 patients with edema refractory to mercurial diuretics. During 13 periods of hyperchloremic acidosis induced by calcium chloride alone or in combination with acetazoleamide, responsiveness to mercurial diuretics was restored. Calcium chloride has proved to be a safe, effective substitute for ammonium chloride as a source of chloride in this regimen. It may be employed in patients with liver disease.

Cardiac aspects of renal disease

Abstract The heart and the kidney are interdependent in the maintenance of circulatory homeostasis. It is not surprising, therefore, that cardiac manifestations are frequently seen in the course of renal disease. Cardiac abnormalities may occur concomitant with renal disease if both share the same basic pathologic process. Cardiac manifestations may also appear as a result of abnormalities in renal function leading to altered fluid and electrolyte balance. In advanced stages of the uremic syndrome anatomic changes in the heart often result. The pathogenesis of many cardiac manifestations in uremia, however, remains obscure. Management of the renal disease is similar in all these processes. The principles as outlined may be applied with minimum laboratory facilities. In maintenance of fluid balance, total daily intake should match total daily loss. Daily measurement of intake and output supplemented by determinations of body weight are readily available, valuable clinical guides. Electrolyte management also involves replacement of specific losses. In complex situations, determination of urinary as well as plasma electrolyte concentrations may prove helpful in calculation of daily needs. Electrolyte abnormalities are most serious in their cardiac effects. The resultant electrocardiographic changes represent the sum total of a complex ion relationship. With changing electrolyte patterns, therefore, frequent electrocardiographic observations are necessary. Specific abnormalities are discussed and illustrated with case examples. The dangers of electrolyte abnormalities and overhydration in the oliguric patient and the basic principles of their management are well recognized. The same principles applied in all phases of renal disease can result in gratifying improvement in useful life expectancy.