Reika Tanaka

Effect of sevelamer and calcium-based phosphate binders on coronary artery calcification and accumulation of circulating advanced glycation end products in hemodialysis patients.

BACKGROUND Some trials have indicated that coronary artery calcification progresses more slowly in sevelamer-treated dialysis patients than in those using calcium-based binders. Effects of phosphate binders on circulating advanced glycation end products (AGEs) are unknown. STUDY DESIGN Randomized trial with parallel-group design. SETTING & PARTICIPANTS 183 adult (aged >20 years) patients on maintenance hemodialysis therapy at 12 dialysis facilities with a mean vintage of 118 ± 89 (median, 108) months. Dialysate calcium concentration was 2.5 mEq/L, and dietary calcium was not controlled. INTERVENTION Patients were randomly assigned to 12 months of treatment with sevelamer (n = 91) or calcium carbonate (n = 92). OUTCOMES & MEASUREMENTS Primary outcome measures were change from baseline in coronary artery calcification score (CACS) determined at study entry and completion using multislice computed tomography and the proportion of patients with a ≥ 15% increase in CACS. Blood parameters were determined at study entry and 2-week intervals, and levels of plasma pentosidine, a representative AGE, were determined at study entry, 6 months, and study completion. RESULTS 79 (86.8%) and 84 (91.3%) patients in the sevelamer and calcium-carbonate arms completed the treatment, respectively. Both binders were associated with an increase in mean CACS: 81.8 (95% CI, 42.9-120.6) and 194.0 (139.7-248.4), respectively (P < 0.001 for both). After adjustment for baseline values, the increase in the sevelamer group was 112.3 (45.8-178) less (P < 0.001). Percentages of patients with a ≥ 15% increase in CACS were 35% of the sevelamer group and 59% of the calcium-carbonate group (P = 0.002). Plasma pentosidine levels increased with calcium carbonate but not [corrected] sevelamer treatment (P < 0.001). Sevelamer use was associated with decreased risk of a ≥ 15% increase in CACS regardless of baseline blood parameters, pentosidine level, and CACS. LIMITATIONS Treatment duration was relatively short, some sevelamer-treated patients (7 of 79) received calcium carbonate, and washout could not be performed. CONCLUSIONS The data suggest that sevelamer treatment slowed the increase in CACS and suppressed AGE accumulation.

Present status and perspectives of bioartificial kidneys.

Currently, hemodialysis is not adequate as a renal replacement therapy because it provides intermittent treatment and does not provide the metabolic function of renal tubules. The next generation of artificial kidney should replace intermittent hemodialysis with continuous hemofiltration and provide the full metabolic function of renal tubules. The current decade has witnessed the development of bioartificial kidneys using artificial membranes and renal tubular epithelial cells. Active transport and metabolic functions were confirmed in the confluent monolayers of tubular cells on artificial membranes. Bioartificial kidneys have succeeded in improving the prognosis of patients with multiple organ dysfunction, presumably by lowering plasma cytokine levels in patients. For successful treatment of chronic renal failure using bioartificial kidneys, it is necessary to overcome some technical hurdles such as improving the antithrombogenic properties of the surface of artificial membranes and prolonging the function of renal tubule cells on an artificial membrane. Transfection of functional protein genes into renal tubule cells enables bioartificial tubule devices to increase their transport capacity and metabolic functions such as digoxin secretion and water transport. The development of wearable roller pumps is also essential for the clinical application of a continuous treatment system.

Can cinacalcet replace parathyroid intervention in severe secondary hyperparathyroidism

A 6‐month observational study was conducted in 61 patients (33 men and 28 women, mean age 54.8 ± 12.4 years) treated with cinacalcet in whom parathyroid intervention was indicated. Thirty‐seven patients had baseline intact parathyroid hormone (iPTH) levels of >500 pg/mL, but only five still had levels this high after 6‐month cinacalcet therapy. No patients had phosphorus (P), calcium (Ca), or iPTH levels within the target range at baseline, but six patients (9.8%) reached all three target ranges after treatment. The stratum with many patients who had 2–4 enlarged parathyroid glands shifted toward the low PTH groups (iPTH < 300 pg/mL) with treatment. There was less of a tendency for patients with more enlarged glands, that is, 10 mm or larger at baseline, to have a higher PTH level after cinacalcet treatment. There was no significant difference in the total volume of parathyroid glands after treatment, since some glands enlarged while others shrank. These findings indicate cinacalcet to be a potentially useful treatment. Our results suggest that 80% of cases indicated for parathyroid intervention could avoid such interventional therapies with cinacalcet administration. However, the variability in the gland‐shrinking effect of cinacalcet on parathyroid glands merits further study.

Suppression of parathyroid hormone production in vitro and in vivo by RNA interference

We used RNA interference, which causes sequence-specific degradation of target mRNAs to suppress the production of parathyroid hormone by cells of patients with secondary hyperparathyroidism in vitro and in vivo. Transfection of small interfering RNA (siRNA) against human parathyroid hormone into monolayers of parathyroid cells cultured from these patients caused a dose-dependent decrease of secretion and mRNA levels with 80% or more suppression using 40 nM siRNA. Parathyroid cells cultured on non-adherent plastic produced spheroid cell aggregates which secreted parathyroid hormone for more than 150 days. Transfection of these spheroids with 50 nM targeted siRNA decreased parathyroid hormone production to 20% of the control level, with half of them being suppressed for 50 days. When parathyroid cells were transplanted into the livers of athymic nude mice, plasma human parathyroid hormone rose to 100-300 pg/ml within one month and remained at about this level for at least 39 days. Systemic delivery of hormone-targeted siRNA into these mice caused a dose-dependent suppression of circulating human parathyroid hormone for at least one month, with a maximum 80% suppression achieved by 80 microg of siRNA. Our study shows that hormone secretion by parathyroid cells of patients with secondary hyperparathyriodism can be suppressed both in vitro and in vivo by targeted siRNAs.

Reversed whole PTH/intact PTH ratio as an indicator of marked parathyroid enlargement: five case studies and a literature review

Parathyroid hormone (PTH) levels detected by intact PTH assays are generally higher than those detected by the whole PTH assay because the latter does not detect non-(1–84) PTH fragments, mainly PTH (7–84). Rare exceptions to this rule have been reported in patients with severe primary or secondary hyperparathyroidism and parathyroid carcinoma. Overproduction of an N-form of PTH other than PTH (1–84) has been observed in the sera of these patients. We report five additional cases with the reversed whole PTH/intact PTH ratio associated with severe hyperparathyroidism in haemodialysis patients. Three patients demonstrated enlargement of a single hypervascular gland, whereas the other two had undergone surgical parathyroidectomy and later showed recurrent hyperparathyroidism due to progressive autograft hyperplasia. In the case of a single enlarged gland, the pathological pattern and heterogeneous expression of parathyroid adenomatosis 1/cyclin D1 suggested it to be a single nodule of uraemic hyperparathyroidism rather than sporadic primary adenoma. These cases suggested that the reversed whole PTH/intact PTH ratio could be an indicator of marked parathyroid enlargement. Further studies are required to elucidate the clinical significance of the reversed whole PTH/intact PTH ratio in haemodialysis patients.

Co-expression of parathyroid hormone and chromogranin A in secondary hyperparathyroidism: a functional marker for secretory activity of hyperplastic nodules.

The relationship between secretion of parathyroid hormone (PTH) and biologic characteristics, including cell proliferation or monoclonality, is not yet fully understood. To evaluate secretory activity of glands or nodules histopathologically, we focused on the co-expression of chromogranin A (CgA) and parathyroid hormone (PTH) in each gland or nodule. A total of 55 glands from 38 patients with normal parathyroid glands, hyperplastic glands (diffuse and nodular) and primary adenomas were compared. Co-expression of PTH and CgA was decreased to 44.4% in diffuse hyperplastic glands, and to 39.6% in 91 hyperplastic nodules, in contrast to normal glands and primary adenomas that showed constant co-expression of PTH and CgA. Immunohistochemical study of PTH showed a coarse granular pattern predominantly in PTH-positive/CgA-positive nodules, and a dot-like pattern mainly in PTH-positive/CgA-negative nodules. Laser scanning microscopy and immunoelectron microscopy confirmed that a dot-like pattern is based on a positive reaction of PTH at the Golgi apparatus. MIB-1 LI was 12.6 +/- 11.6 in PTH-positive/CgA-positive, and 19.3 +/- 27.3 in PTH-positive/CgA-negative nodules. In conclusion, a combination of PTH and CgA could provide more information about the physiologic state of secretory activity of each nodule than does the simple observation of PTH immunoreactivity.

Indication and efficacy of PEIT in the management of secondary hyperparathyroidism.

Control of secondary hyperparathyroidism (SHPT) using active vitamin D analogues becomes difficult in advanced SHPT, because the enlarged parathyroid glands (PTGs) are resistant to medical therapy. Percutaneous ethanol injection therapy (PEIT) has been widely used in Japan since the 1990s as a surgical intervention for advanced SHPT, by selectively destroying only the enlarged glands with nodular hyperplasia (i.e. >0.5 cm3, measured by ultrasonography). If there is only one PTG with nodular hyperplasia, PEIT will be successful with a small number of injections, and it then becomes possible to maintain target levels of parathyroid hormone by treatment with active vitamin D analogues. Recent studies have demonstrated that in the advanced phase of SHPT, it is desirable to perform PEIT when it is restricted to patients with not more than one PTG larger than 0.5 cm3 in terms of superior prognosis can be obtained including efficacy, low recurrence, and long-term remission period.

Long-term prognosis of parathyroid function in chronic dialysis patients after PEIT-a single-centre trial

Background. Secondary hyperparathyroidism (SHPT) is a common complication observed in long-term dialysis patients. Percutaneous ethanol injection therapy (PEIT) of parathyroid glands (PTGs) is now established in Japan as a treatment option for SHPT. In this study, to elucidate the factors influencing efficacy in 1 year and relapse following PEIT, we analysed the long-term prognosis of parathyroid function that is known to have the greatest effect on therapeutic results. Methods. The study design was a retrospective cohort study. We studied 104 patients with SHPT, who underwent PEIT at Tokai University Hospital between January 1993 and December 2002, and we followed them up until January 2008. The effective group reached intact parathyroid hormone of 200 pg/ml or less, corrected calcium (Ca) of 10.5 mg/dl or less and phosphate (P) of 6.0 mg/dl or less. The ineffective group failed to achieve these criteria. Results. Among the 104 patients, 66 patients (63%) fulfilled the criteria for the effective group within the first year of PEIT. Using the multivariate logistic regression analysis, the number of PTGs before PEIT was a significant risk factor to deviate from the criteria. At the end of the surveillance period, 31 patients (30%) fulfilled the criteria, and their SHPT was controlled with PEIT. Using the multivariate logistic regression analysis, more than three PTGs at the beginning, and the increase in PTGs during the observation period were significant risk factors to deviate from the criteria. In conclusion, superior results with PEIT are obtained in terms of efficacy, remission period and risk of relapse, regardless of the size of the gland.