Parathyroid hormone-producing cells exist in adipose tissues surrounding the parathyroid glands in hemodialysis patients with secondary hyperparathyroidism.

Possible ectopic parathyroid hormone (PTH) production in adipose tissues surrounding hyperplastic parathyroid glands was examined in patients with secondary hyperparathyroidism (SHPT). In vitro culture of adipose tissues from 31 patients excised during parathyroidectomy showed PTH secretion in 23 (74.2%) patients. In vitro PTH secretion was detected in adipose tissues adhered to the parathyroid glands from 22 (71.0%) patients, in not-adhered adipose from 11 (35.5%) and in the thymus from four (28.6%) patients. Immunohistochemistry revealed colonies of PTH- and GCM2-positive cells intricately intertwined with adipocytes in excised adipose tissues prior to culture. When pieces of parathyroid parenchyma from SHPT patients were transplanted into the thyroid of immunodeficient nude rats with induced SHPT, the transplants secreted human PTH for one to three-and-half months after transplantation and expressed adipocyte markers, PPARγ2 and perilipin A, that the transplants did not express prior to transplantation. These findings indicate the importance of thoroughly removing adipose tissues surrounding the parathyroid glands when performing parathyroidectomy. We speculate that these ectopic PTH-producing cells are parathyroid parenchymal cells pushed out from the glands along with adipocyte progenitors during nodular growth of hyperplastic parenchymal cells and that these cells proliferate in SHPT, forming colonies PTH-producing cells intricately intertwined with adipocytes.

Feasibility of photodynamic therapy for secondary hyperparathyroidism in chronic renal failure rats.

BACKGROUND: Feasibility of photodynamic therapy (PDT) for secondary hyperparathyroidism (SHPT) was examined in a rat model of SHPT. METHODS: A photosensitizer, 5-aminolevulinic acid (5-ALA), was injected intraperitoneally, and the parathyroid glands were irradiated either after surgical exposure with 385-nm light or transdermally with 630-nm light from a light-emitting diode (LED) lamp. RESULTS: PDT with high 5-ALA and irradiation doses caused severe hypoparathyroidism in SHPT rats within two days. Low-dose invasive PDT reduced intact parathyroid hormone (iPTH) levels in all rats from 748.9 ± 462.6 pg/mL at baseline to 138.7 ± 117.5 pg/mL at week 6, followed by a further decrease to 80.5 ± 54.0 pg/mL at week 9 in 60 % of rats or an increase to 970.0 ± 215.6 pg/mL at week 9 in 40 % of rats. Low-dose noninvasive PDT reduced iPTH levels from 1612.5 ± 607.8 pg/mL at baseline to 591.9 ± 480.1 pg/mL at week 4 in all rats. Thereafter, iPTH levels remained low in 43 % of rats and were 233.7 ± 51.6 pg/mL at week 9, whereas 57 % showed an increase, reaching 3305.9 ± 107.3 pg/mL at week 9. Control SHPT rats had iPTH levels of 2487.8 ± 350.9 and 2974.6 ± 372.1 pg/mL at week 4 and 9, respectively. The parathyroid glands of the rats with low iPTH levels were atrophied and had few parathyroid cells surrounded by fibrotic materials and no recognizable blood vessels. Those of the rats with high iPTH levels showed well-preserved gland structure, clusters of parathyroid cells, and blood vessels. CONCLUSION: These results demonstrate that 5-ALA-mediated PDT for SHPT is feasible.

Effect of Scavenging Circulating Reactive Carbonyls by Oral Pyridoxamine in Uremic Rats on Peritoneal Dialysis.

Pyridoxamine, a reactive carbonyl (RCO) scavenger, can ameliorate peritoneal deterioration in uremic peritoneal dialysis (PD) rats when given via dialysate. We examined the effects of scavenging circulating RCOs by oral pyridoxamine. Rats underwent nephrectomy and 3 weeks of twice daily PD either alone or with once daily oral pyridoxamine. PD solution was supplemented with methylglyoxal, a major glucose-derived RCO, to quench intraperitoneal pyridoxamine. Oral pyridoxamine achieved comparable blood and dialysate pyridoxamine concentrations, suppressed pentosidine accumulation in the blood but not in the mesenterium or dialysate, and reduced the increases in small solute transport and mesenteric vessel densities, with no effects on submesothelial matrix layer thickening or serum creatinine. Thus, reducing circulating RCOs by giving oral pyridoxamine with PD provides limited peritoneal protection. However, orally given pyridoxamine efficiently reaches the peritoneal cavity and would eliminate intraperitoneal RCOs. Oral pyridoxamine is more clinically favorable and may be as protective as intraperitoneal administration.

Association between Asymmetric Dimethylarginine and Pentosidine in Dialysis Effluent of Peritoneal Dialysis Patients -A possible intraperitoneal crosstalk between asymmetric dimethylarginine and advanced glycation end products in peritoneal dialysis patients.

OBJECTIVE: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase. Elevated serum ADMA concentration is associated with impaired vascular endothelial function. We examined the relationships of ADMA with pentosidine, a representative advanced glycation end product, cytokines and the markers of peritoneal inflammation, damage and repair in dialysate effluent of peritoneal dialysis patients. METHODS: Study design was cross-sectional. Twenty-eight peritoneal dialysis patients who were ≥ 18 years of age, had been on peritoneal dialysis for at least 3 months and had no history of renal transplantation were enrolled. Dialysis effluent and blood were sampled after 8 hours of peritoneal dialysis. Concentrations of ADMA, pentosidine, cytokines and the markers of peritoneal inflammation, damage and repair were determined in dialysis effluent. Blood samples were analyzed for routine laboratory parameters. RESULTS: The effluent ADMA level had a significant correlation with effluent pentosidine concentration (R=0.511, P=0.005), but not with interleukin-6, interleukin-8, transforming growth factor-α, hyaluronic acid, cancer antigen 125 or fibrinogen/fibrin degradation products. CONCLUSION: In the light of available evidence, our results suggest that AGEs generated during dialysate dwelling alters ADMA metabolism in the peritoneal tissues, leading to ADMA accumulation in the peritoneal cavity.

Cinacalcet induces apoptosis in parathyroid cells in patients with secondary hyperparathyroidism: histological and cytological analyses.

BACKGROUND/AIMS: Previous studies reported a reduction in parathyroid gland volume during treatment with cinacalcet in patients with secondary hyperparathyroidism (SHPT). However, it remains to be determined whether cinacalcet accelerates apoptosis of hyperplastic parathyroid cells in these patients. METHODS: The study subjects were 16 hemodialysis patients who had undergone parathyroidectomy for severe SHPT. We compared the expression of the apoptotic marker TUNEL and the proliferative marker Ki67 by immunohistochemistry and the expression of CYP27B1 by quantitative real-time PCR in hyperplastic parathyroid glands from patients treated with cinacalcet (cinacalcet group; n = 8) and those not treated with cinacalcet (non-cinacalcet group; n = 8). We also examined the effect of cinacalcet on parathyroid cell death in in vitro cell culture with TUNEL staining, using parathyroid cells from SHPT patients. RESULTS: Compared with the non-cinacalcet group, the expression of TUNEL was significantly increased but was accompanied with significantly increased Ki67 expression in the parathyroid glands from the cinacalcet group. In vitro examination showed dose- and time-dependent increases of apoptotic cells by adding cinacalcet into culture medium. We also found that the expression of CYP27B1 showed a three-fold increase in glands from the cinacalcet group compared to that of the non-cinacalcet group. CONCLUSION: Our data suggest that cinacalcet induces apoptosis of human parathyroid cells, but this effect may be overcome by more aggressive proliferation of parathyroid cells in patients with severe, cinacalcet-resistant SHPT.

Evaluation of bioartificial renal tubule device prepared with lifespan-extended human renal proximal tubular epithelial cells.

BACKGROUND: Acute kidney injury (AKI), accompanied by the development of systemic inflammatory response syndrome and multiorgan dysfunction syndrome, is associated with a high risk of death. Bioartificial renal tubule device (BTD) is a cell therapy that improves the conditions common to artificial kidney recipients treated for kidney diseases. In this paper, we describe the establishment of BTD with lifespan-extended human renal proximal tubular epithelial cells. METHODS: AKI goats were established by performing bilateral nephrectomy followed by lipopolysaccharide administration. The AKI goats were treated with BTD or sham-BTD, and the two groups of animals were compared by measuring the respective life spans and the levels of blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and serum electrolytes. The expression levels of inflammatory cytokines were detected by reverse transcription-polymerase chain reaction, and plasma interleukin (IL)-6 levels were measured by enzyme-linked immunosorbent assay. RESULTS: The life span of AKI goats was extended: the lifetime with the BTD treatment compared with sham-BTD. BTD and sham-BTD showed a similar degree of small solute clearance. The expression levels of inflammatory cytokines and plasma IL-6 levels were decreased by the BTD treatment. CONCLUSIONS: BTD treatment results in less damage from endotoxin shock and increased life span in AKI goats. These results suggest that BTD may be a useful component of bioartificial kidneys and should be considered in the next generation of renal replacement therapies.

Improved response of growth hormone to growth hormone-releasing hormone and reversible chronic thyroiditis after hydrocortisone replacement in isolated adrenocorticotropic hormone deficiency.

We report a 44-year-old Japanese man who showed a reversible blunted response of growth hormone (GH) to GH-releasing hormone (GRH) stimulation test and reversible chronic thyroiditis accompanied by isolated ACTH deficiency. He was admitted to our hospital because of severe general malaise, hypotension, and hypoglycemia. He showed repeated attacks of hypoglycemia, and his serum sodium level gradually decreased. Finally, he was referred to the endocrinology division, where his adrenocorticotropic hormone (ACTH) and cortisol values were found to be low, and his GH level was slightly elevated. An increased value of thyroid stimulating hormone (TSH) and decreased values of free triidothyronine and free thyroxine were observed along with anti-thyroglobulin antibody, suggesting chronic thyroiditis. Pituitary stimulation tests revealed a blunted response of ACTH and cortisol to corticotropin-releasing hormone, and a blunted response of GH to GRH. Hydrocortisone replacement was then started, and this improved the patient's general condition. His hypothyroid state gradually ameliorated and his titer of anti-thyroglobulin antibody decreased to the normal range. Pituitary function was re-evaluated with GRH stimulation test under a maintenance dose of 20 mg/day hydrocortisone and showed a normal response of GH to GRH. It is suggested that re-evaluation of pituitary and thyroid function is useful for diagnosing isolated ACTH deficiency after starting a maintenance dose of hydrocortisone in order to avoid unnecessary replacement of thyroid hormone.

New method of blood purification (Recycle Filtration System).

OBJECT: We have developed a new blood purification system, the Recycle Filtration System (RFS), because back contamination of endotoxin (ET) from the dialysate in on-line hemodiafiltration (HDF) is a potential problem when a highly permeable membrane is used. METHODS: When the RFS is used for HDF, some of the purified fluid is pumped by a purified fluid pump to the venous side of the blood circuit, and the remainder is returned to the filtrate side of the hemofilter to be used for diffusion. This circuit enables simultaneous diffusion and filtration through the hemofilter. RESULTS: 1. The rate of removal of urea nitrogen (UN) increased with either decreased or increased quantity of recycled filtration flow (QRF). The rate of removal of beta-2-microglobulin (ß2-MG) decreased as QRF increased, but its clearance and removal rate increased as the quantity of drainage flow increased. 2. No significant change in ß2-MG clearance was observed in the filtration unit, even when recycling was continued for 24 h. 3. ET was not detected in the filtration unit, even though its level in the dialysate, which was reconstituted with tap water, was 806.2±105.4 EU/L. CONCLUSION: It is possible to regulate filtration using the RFS by giving importance to the elimination of either small molecules or low-molecular-weight proteins.