Middle molecules in uremic patients have been presumed being responsible for certain uremic symptome. However, study on the uremia middle molecules has not been yet satisfactorily performed. Present experimental study was undertaken to clarify clinical significance of middle molecules in uremia. Uremic and normal sera were ultrafiltrated using Amicon Diafromembrane PM10(R), which has a molecular cut-off at about 10, 000. Solutes in the ultrafiltrated sera were divided according to their molecular weight by molecular filtration method with Sephadex G15 column, 90 × 0.6cm, and 0.01 mol Tris HCl elution buffer p118. 6. Toxicity of the middle molecules to living cells was examined, while blastformation of normal lymphocytes mixed with the middle molecules was checked by ³H-Thymidine uptake. Results obtained were as follows: 1. Solutes in the ultrafiltrated uremic sera were divided into 8 to 10 peaks at 278, 254 or 206 nm by the present method. 2. The middle molecules, which were not observed in normal subjects, were present in the second peak on the gel chromatogram. 3. Uremic middle molecular peak 2 (U-MMP2), which was tentatively named, was further divided into 5 to 8 subpeaks by gradient elution chromatography on DEAF 25A. 4. Amino acid analysis of U-MMP2 or subpeaks of U-MMP2 before and after acid hydrolysis demonstrated that U-MMP2 was a mixture of oligopeptide consisting mainly of Asp, Gly and Glu. 5. The U-MMP2, not either creatinine or urea, was often found markedly in uremic dialyzed patients with complications such as intractable pyrexia, sepsis, pericarditis and malnutrition. 6. As the concentration of the U-MMP2 increased as much as 2 to 4 times of mean values of regular hemodialysis patients, inhibitory effect on 3H-Thymidine uptake of cultivated lymphocytes became apparent. 7. Lymphocytes pretreated with U-MMP2 for 120 minutes responded to phytohemagglutinin almost similarly as control, However, the lymphocytes, for which pretreatment time had been prolonged over 8 hours, showed low uptake of ³H-Thymidine in spite of U-MMP2 washing-out. 8. Administration of U-MMP2 suppressed ³H-Thymidine uptake of lymphocytes, even if added to the medium after 6 hours from the start of cultivation. 9. The inhibitory effect of U-MMP2 on blastformation may be caused by nonspecific injury to viability of the lymphocytes.

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A 43 year-old woman, who was found to have renal tubular acidosis (RTA) at the age of 30, developed Sjögren's Syndrome during a long-term follow-up observation. In, she was admitted to the hospital because of thirst, polyuria and general malaise. She had hypokalemia, metabolic acidosis and poor renal acidification. The urine-concentrating capacity was reduced without glycosuria or aminoaciduria. PSP test, C_PAH and C_Cr were normal. Although she had accelerated erythrocyte sedimentation rate, positive rheumatoid factor and hypergammaglobulinemia, arthritis and sicca syndrome were absent. Thus she was diagnosed as having RTA, the cause of which was not clear. She was maintained well on the alkaline therapy. Renal calcification was noticed on the abdominal X-ray film in 1967, and polyarthitis and sicca syndrome appeared in 1973. She was re-admitted to the hospital for the detailed examination in October, 1975. Subcutaneous nodules in the elbow which was histologically characteristic of rheumatoid arthritis, positive Rose-Bengal test, and cystic and destructive changes in the sialography suggested that she had Sjögrens Syndrome. The BUN and serum creatinine were within normal range and the CPAH was 10% less than at the first admission. The renal biopsy revealed dilatation of the tubules and flattening of the epithelial cells, but no particular changes in the interstitial space. Thus, RTA could be considered one of the initial signs and symptoms of Sjögren's Syndrome in this patient. The deterioration in renal function were slowly progressive in spite of the appearance of nephrocalcinosis. The relationship between nephrocalcinosis and the alkaline therapy remains obscure.

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The perfusion experiment was performed to clarify the mechanism of potassium transport and factors of regulating potassium secretion in the rat intestine. Na and K equilibrium concentration, electrical potential difference (PD) and fecal Na and K contents were measured. In addition, Na and K balance study were carried out in patients with chronic uremia. The following results were obtained. 1) In the control rat, chronic potassium load increased potassium secretion, sodium absorptionn and PD in the colon, whereas no changes were observed in the jejunum and ileum, Fecal Na/K ratio was also decreased by potassium load. 2) K net flux was similar in the rat small intestine of control and experimental renal failure (RF). 3) In the colon of RF rat, chronic potassium load increased potassium secretion, sodium absorption and PD, which suggests a same mechanism for potassium secretion process in the colon of normal rat with potassium load. This potassium secretion rate fell when Na-free choline chloride solution was perfused. Increased potassium secretion in the colon was inhibited by spironolactone and this results suggest that potassium secretion in the colon is mediated by aldosterone. Fecal excretion of potassium in the RF rat plays an important role in maintaining potassium balance. 4) Aldosterone increased potassium secretion, sodium absorption and PD in the colon of adrenalectomized rat, but no effect was observed in the jejunum and ileum. Increased fecal excretion of potassium and decreased fecal Na/K ratio were also found. These data suggests that aldosterone plays an important role in regulating potassium secretion in the colon. 5) Increased fecal potassium excretion indicates an important extra-renal excretory pathway for the purpose of maintaining potassium balance in patients with renal failure.

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