The association of the angiotensinogen (AGT) gene variation at codon 235, the T235 variant, with hypertension induced by erythropoietin (Epo) was investigated in patients with progressive renal disease requiring treatment for renal anemia with Epo. The subjects for the study were patients with renal diseases with serum creatinine concentration exceeding 2 mg/dl and a hematocrit (Ht) of less than 30%. During the run-in period, blood pressure was well controlled with an appropriate salt restricted diet and/or antihypertensive treatment. The patients were then given 6,000 IU of Epo once a week until the Ht rose by 5%. For the overall patient group, AGT gene polymorphism analysis revealed T235T (T/T) in 31 cases (61%), M235T (M/T) in 19 cases (37%), and M235M (M/M) in 1 case (2%). In response to treatment with Epo, hypertension (defined as an increase in mean blood pressure greater than 10 mmHg) was found in 11 cases (22%), all of who carried the homozygous T allele (T/T). On the other hand, the frequency of T/T in patients who did not develop hypertension was 50% (T/T:T/M=20:19 cases), indicating a significant difference (p=0.003 by Chi-square). Variables estimated to be associated with Epo-induced hypertension were the T allele, gender (male), and the degree of increase in Ht, in descending order. Our preliminary research indicates that individuals who carry two copies of the T allele, i.e., who are homozygous for T, are highly susceptible to development of hypertension when subjected to Epo. These results suggest that the AGT T235 variant may be the primary gene responsible for the development of Epo-induced hypertension.

Wereport here a rare case of 47 XXY/46 XYmosaic Klinefelter's syndromeassociated with multiple endocrine disorders. A 35-year-old male admitted for the evaluation of renal dysfunction and recurrent bone fractures was diagnosed as having Klinefelter's syndrome by endocrinological examinations and sex chromosomeanalysis. He has suffered from diabetes mellitus for morethan ten years. The serum FSHand LH levels were high together with low free testosterone and estradiol levels. There was a discrepancy between basal serum GHand somatomedin-C levels. On admission, thyroid function revealed thyrotoxicosis with low radioactive iodine uptake and negative thyroid autoantibodies. During hospitalization, serum FT3 and FT4 levels were gradually decreased and serum TSHlevels became elevated, leading to the diagnosis of subacute thyroiditis. Serum ACTH levels showed high basal levels with delayed, exaggerated responses to insulin-induced hypoglycemia. Rapid ACTHtest (1 24ACTH0.25 mg) showed low cortisol responses and many of the adrenocortical steroids in plasma and urine were low or low normal. Furthermore, bone mineral density (BMD) by DEXAshowed marked osteoporosis. Possible mechanisms underlying these varied endocrine disorders remain to be elucidated. (Internal Medicine 35: 396-402, 1996)

A 20-year-old womanwith IgA nephropathy was admitted to Jikei University Hospital for the treatment of rapid deterioration of renal function after receiving 131I-therapy against hyperthyroidism on October 23, 1999, and hemodialysis was started. On admission, she was diagnosed as having Evans' syndrome in addition to known Graves9 disease. Renal biopsy revealed end-stage renal damage, then, hemodialysis was maintained. Treatment for Evans9 syndromewas also started and her general condition gradually improved. The present case implied that "Graves9 disease99 and "Evans9 syndrome99 could represent some of the manifestations of an underlying immunological disorder in the patient.

To investigate the differences in the Na-K transport of the mesangial cell (MC) membrane in hypertension versus normotension, the activity of the Na-K pump and the passive cation permeability were measured in serially passaged cultured MC obtained from both spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. When Na-K pump was active, Na-K pump activity, described as ouabain-sensitive ⁸⁶Rb uptake, was significantly greater in the cultured MC from SHR than WKY rats. The outward Na-K cotransport, described as the washout rate constant of bumetanide-sensitive ⁸⁶Rb washout, was also greater in SHR MC than in WKY rat MC. When Na-K pump was inhibited by 1 mM ouabain, overall intracellular Na uptake was significantly greater in SHR MC. A greater 5-(N, N-hexamethylene)amiloride-sensitive Na uptake in SHR MC accounted for this difference. There was no difference in the intracellular concentration of Na and K in the cultured MC from the 2 strains when Na-K pump was active. It is concluded that there is an increased activity of Na-K pump in the cultured MC from SHR, and that this abnormality may be innate to SHR cells. It is also suggested that an increase in Na-K cotransport and Na-H antiport may explain this difference, and that these abnormalities observed in the SHR kidney may be involved in the pathogenesis of hypertension in this model.

Levels of adrenomedullin (AM) have been shown to be elevated in hypertension and chronic renal failure,suggesting that AM plays a role in the pathogenesis of these diseases. The objective of the present study was to investigate whether circulating AM is involved in erythropoietin (Epo)-induced hypertension in patients with renal anemia due to progressive renal disease. Following treatment with 6,000 IU of Epo once a week, the hematocrit (Ht) rose significantly from 25.9±4.0 to 33.4±3.3% (n=54, p<0.001) with an overall rate of increase in Ht of 0.43±0.04%/week. In response to treatment with Epo, a rise in mean blood pressure of >10 mmHg (Epo-induced hypertension) was found in 22% (12/54 cases) of the patients enrolled.There was no difference in the rate of Ht increase between patients with and without Epo-induced hypertension. There was a significant positive correlation between mature AM and serum creatinine (Cr) concentration before treatment with Epo. However, no correlation was found between the plasma concentration of total AM and serum Cr concentration. Long-term treatment with Epo did not influence plasma concentration of either mature AM or total AM in patients developing hypertension during the study period. These results suggest that circulating AM may play a role in the progression of renal disease. However, the present study does not support the notion that circulating AM is associated with the pathogenesis of Epo-induced hypertension. It is too early yet to claim that there is no AM-mediated mechanism in Epo-induced hypertension. (Hypertens Res 2000; 23: 427-432)