Comparison of postoperative biomechanical function between anatomic double-bundle and single-bundle ACL reconstructions using calcium phosphate-hybridized tendon grafts in goats.

BACKGROUND: Calcium phosphate (CaP)-hybridized tendon grafts improved biomechanical function compared with untreated grafts after single-bundle (SB) anterior cruciate ligament (ACL) reconstruction. The purpose of this study was to compare the biomechanical function between anatomic double-bundle (DB) and single-bundle (SB) ACL reconstructions using CaP-hybridized tendon grafts at 6 months postoperatively in goats. HYPOTHESIS: We hypothesized that the postoperative biomechanical function in the DB group will be better than that in the SB group. MATERIALS AND METHODS: Knee kinematics and in situ forces in the grafts under applied anterior tibial load (ATL) of 50N and internal tibial torque (ITT) of 2.0 Nm at full extension, and 60° and 90° of knee flexion, and the histology of the tendon-bone interface were compared between the DB group (n=6) and SB group (n=6). RESULTS: The in situ forces under ATL in the DB group at full extension and 90°of knee flexion were greater than those in the SB group. The in situ forces under ITT in the DB group at full extension and 60°of knee flexion were greater than those in the SB group. The in situ forces on the posterolateral bundle of the grafts under ATL and ITT in the DB group at full knee extension were greater than those on the posterior half of the grafts in the SB group. The histology did not differ significantly between the groups. CONCLUSIONS: Although CaP-hybridized tendon grafts were used in both groups, the in situ forces under ATL and ITT in the DB group were greater than those in the SB group at 6 months postoperatively. The posterolateral bundle of the grafts in the DB group acted effectively against both ATL and ITT at full extension. The tendon-to-bone healing was similar in both groups. STUDY DESIGN: Controlled laboratory study. Level 2.

Two cases of nephrotic syndrome (NS)-induced acute kidney injury (AKI) associated with renal hypouricemia.

Renal hypouricemia is a clinical disorder attributed to an increased renal urate excretion rate and is well known to involve a high risk of urolithiasis and exercise-induced acute kidney injury (AKI). This report concerns two interesting cases of nephrotic syndrome (NS)-induced AKI associated with renal hypouricemia. A 64-year-old female (Case 1) and a 37-year-old male (Case 2) were hospitalized because of AKI (serum creatinine: 2.07 mg/dl and 3.3 mg/dl, respectively), oliguria and NS. They were treated with prednisolone and temporary hemodialysis. Renal function improved, but hypouricemia persisted during hospitalization. Histological findings in both cases led to a diagnosis of minimal change nephrotic syndrome and identification of the diuretic phase of tubulointerstitial damage because of findings such as acute tubular necrosis. Furthermore, distal tubules of Case 2 showed an amorphous mass, possibly a uric acid crystal. Analysis of the two cases with the URAT1 gene, encoded by SLC22A12, found a homozygous mutation in exon 4 (W258stop) of each one. Our cases show that patients with renal hypouricemia may be susceptible to AKI without involvement of exercise if they possess some facilitators. Renal hypouricemic patients should therefore be carefully examined for all complications from renal hypouricemia because of high risk of AKI.

Homocysteine and folic acid levels in hemodialysis patients treated with sevelamer hydrochloride.

BACKGROUND/AIMS: Folic acid deficiency has been reported to elevate plasma homocysteine levels and result in hyperhomocystinemia, which is an independent risk factor for cardiovascular disease. Sevelamer hydrochloride has the potential to bind with folic acid. To determine this effect of sevelamer hydrochloride on plasma homocysteine levels, change in serum folic acid and plasma homocysteine levels after administration of sevelamer hydrochloride in chronic hemodialysis patients was evaluated. METHODS: Sevelamer hydrochloride was administered to 26 outpatients undergoing hemodialysis for 3 months. Serum and plasma samples were collected just before the dialysis session at baseline and 3 months. RESULTS: Three months after the administration of sevelamer hydrochloride, serum folic acid levels significantly decreased (baseline vs. 3 months; 5.48 +/- 1.81 vs. 4.79 +/- 1.79 ng/ml, p < 0.05), whereas plasma homocysteine levels significantly increased (baseline vs. 3 months; 50.8 +/- 35.9 vs. 67.6 +/- 44.7 nmol/ml, p < 0.01). CONCLUSION: These findings suggest that sevelamer hydrochloride elevates plasma homocysteine levels, possibly by inhibiting the absorption of folic acid. Thus, the effect of sevelamer hydrochloride should be excluded while evaluating the increased plasma levels of homocysteine.

FGF23: a key player in mineral and bone disorder in CKD.

FGF23 is a recently identified hormone regulating mineral and vitamin D metabolism. In patients with chronic kidney disease (CKD), circulating FGF23 levels are progressively elevated to compensate for persistent phosphate retention, which result in reduced renal production of 1,25-dihydroxyvitamin D and thereby stimulate secretion of parathyroid hormone, suggesting its critical role in the pathogenesis of altered mineral homeostasis in CKD. Furthermore, it has recently been shown that FGF23 directly acts on parathyroid gland and mediate secretion of parathyroid hormone in the presence of Klotho as a cofactor, although such effects are not yet confirmed in patients with CKD. FGF23 can also be used as a predictor of mortality as well as future development of refractory hyperparathyroidism in patients undergoing dialysis therapy, where FGF23 levels are markedly elevated in response to hyperphosphatemia and active vitamin D treatment. This brief review summarizes recent insights into the role of FGF23 in the pathogenesis of mineral and bone disorders in CKD.

FGF23: a key player in mineral and bone disorder in CKD

El FGF23 es una hormona de reciente identificación que regula el metabolismo de los minerales y de la vitamina D. En pacientes con insuficiencia renal crónica (IRC), los niveles circulantes de FGF23 se elevan de forma progresiva para compensar la retención renal de fosfato persistente, lo cual provoca una producción renal reducida de 1,25-dihidroxivitamina D y estimula, por tanto, la secreción de la hormona paratifoidea. Este hecho sugiere que su papel es crucial en la patogénesis de la homeostasis mineral alterada en la IRC. Asimismo, se ha demostrado recientemente que el FGF23 actúa directamente en la glándula paratiroidea y media en la secreción de la hormona paratiroidea en presencia del Klotho como cofactor, aunque hasta el momento dichos efectos no se han confirmado en pacientes con IRC. El FGF23 también puede utilizarse como predictor de la mortalidad así como de un futuro desarrollo de hipertiroidismo refractario en pacientes sometidos a diálisis, en los que los niveles de FGF23 son realmente elevados como reacción al tratamiento de hiperfosfatemia y a la actividad de la vitamina D. En este resumen breve se incluyen las aproximaciones más recientes en cuanto al papel del FGF23 en la patogénesis de las alteraciones del metabolismo óseo-mineral en la IRC (AU)

FGF23 is a recently identified hormone regulating mineral and vitamin D metabolism. In patients with chronic kidney disease (CKD), circulating FGF23 levels are progressively elevated to compensate for persistent phosphate retention, which result in reduced renal production of 1,25-dihydroxyvitamin D and thereby stimulate secretion of parathyroid hormone, suggesting its critical role in the pathogenesis of altered mineral homeostasis in CKD. Furthermore, it has recently been shown that FGF23 directly acts on parathyroid gland and mediate secretion of parathyroid hormone in the presence of Klotho as a cofactor, although such effects are not yet confirmed in patients with CKD. FGF23 can also be used as a predictor of mortality as well as futured evelopment of refractory hyperparathyroidism in patients undergoing dialysis therapy, where FGF23levels are markedly elevated in response to hyperphosphatemia and active vitamin D treatment. This brief review summarizes recent insights into the role of FGF23 in the pathogenesis of mineral and bone disorders in CKD (AU)

The making of a bone in blood vessels: from the soft shell to the hard bone.

Vascular calcification, particularly of the medial layer of arteries, is one of the key determinants of survival in patients with chronic kidney disease. This abnormality is not merely a simple process of precipitation of calcium and phosphate but also includes several mechanisms similar to those of bone formation within the vessel wall.

Low-calcium dialysate improves mineral metabolism in hemodialysis patients.

BACKGROUND: The Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommend 1.25 mmol/l Ca dialysate for both hemodialysis and peritoneal dialysis, while 1.5 mmol/l Ca dialysate has been used in our dialysis center. METHODS: Therefore, we switched the dialysate calcium concentration from 1.5 - 1.25 mmol/l and observed the effects on serum calcium (S-Ca), phosphorus (S-P), 1-84 parathyroid hormone (whole PTH, w-PTH), bone-specific alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) for 6 months in 58 hemodialysis patients. Prescription of active vitamin D (VD) metabolites and Ca carbonate was increased in response to the changes in laboratory data. RESULTS: Decrease of S-Ca was evident at 2 weeks and S-Ca remained low for 6 months. Transient elevation of S-P, which might be caused by stimulated bone resorption, was observed after the switch. In patients with low PTH (w-PTH less than 90 pg/ml before the switch), continuous increase of w-PTH, BAP, and TRACP-5b was observed. This appeared to be a favorable response because the risk ofadynamic bone disease was high in this group of patients. On the other hand, acute elevation of the 3 parameters was well-controlled in patients with moderate and high PTH (w-PTH from 90 - 180 pg/ml, w-PTH more than 180 pg/ml, respectively) by increased dosage of active VD. CONCLUSION: These results demonstrate that 1.25 mmol/l Ca dialysate improved mineral metabolism by lowering S-Ca and releasing oversuppression of PTH. Our data also suggest that appropriate use of active VD could prevent acute rise of PTH.

Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells.

Skeletal resistance to parathyroid hormone (PTH) is well known to the phenomenon in chronic renal failure patient, but the detailed mechanism has not been elucidated. In the process of analyzing an animal model of renal failure with low bone turnover, we demonstrated decreased expression of PTH receptor (PTHR) accompanying renal dysfunction in this model. In the present study, we focused on the accumulation of uremic toxins (UTx) in blood, and examined whether indoxyl sulfate (IS), a UTx, is associated with PTH resistance. We established primary osteoblast cultures from mouse calvariae and cultured the cells in the presence of IS. The intracellular cyclic adenosine 3',5' monophosphate (cAMP) production, PTHR expression, and free radical production in the primary osteoblast culture were studied. We found that the addition of IS suppressed PTH-stimulated intracellular cAMP production and decreased PTHR expression in this culture system. Free radical production in osteoblasts increased depending on the concentration of IS added. Furthermore, expression of organic anion transporter-3 (OAT-3) that is known to mediate cellular uptake of IS was identified in the primary osteoblast culture. These results suggest that IS taken up by osteoblasts via OAT-3 present in these cells augments oxidative stress to impair osteoblast function and downregulate PTHR expression. These finding strongly suggest that IS accumulated in blood due to renal dysfunction is at least one of the factors that induce skeletal resistance to PTH.

Basic and clinical aspects of parathyroid hyperplasia in chronic kidney disease.

Marked parathyroid hyperplasia develops in patients with chronic kidney disease, especially those with long dialysis vintage. Although progression of hyperplasia is associated with downregulation of vitamin D receptor and calcium-sensing receptor, initial abnormality that triggers and maintains parathyroid cell proliferation, as well the critical abnormality for the progression of diffuse hyperplasia to nodular hyperplasia, still remains to be elucidated. It is quite important for the optimal management of renal osteodystrophy to recognize the development of nodular hyperplasia, because the cells in nodular hyperplasia are usually resistant to medical therapy and further treatment of such patients often leads to vascular calcification. For this purpose, size and blood supply of enlarged parathyroid glands have been used as good clinical markers. Furthermore, we have recently shown that the serum fibroblast growth factor 23 level can be used for predicting refractory hyperparathyroidism. Once nodular hyperplasia develops in any of the enlarged parathyroid glands, such patients need to be treated by parathyroid intervention including percutaneous ethanol injection therapy. In addition, as direct vitamin D injection therapy has been shown to induce regression of hyperplasia, it may become possible to reverse or normalize established nodular hyperplasia if we can develop new agents with such effects in the near future.

Insufficiency of PTH action on bone in uremia.

Abnormal bone turnover and mineral metabolism is observed in patients on dialysis. Secondary hyperparathyroidism (SHP) develops in response to mineral metabolism changes accompanying renal failure. As a factor of disease progression, the phenomenon of skeletal resistance to parathyroid hormone (PTH) is observed. With recent advances in the treatment of SHP, over-secretion of PTH can now be controlled. However, blood PTH levels 2 to 3 times higher than normal are considered necessary to maintain normal bone turnover in patients with renal failure. Various causes of skeletal resistance to PTH have been reported, including decrease in PTH receptor in osteoblasts, accumulation of 7-84 PTH fragment, and accumulation of osteoprotegerin. This skeletal resistance to PTH is not only a high-turnover bone accompanying SHP, but may also play a crucial role in the onset of low-turnover bone disease. We have produced a rat model of renal failure with normal level of PTH secretion and analyzed the bone of this model. Our results confirmed that bone turnover is lowered accompanying renal function impairment. We also found that this lowered bone turnover is improved by intermittent administration of PTH. In addition, PTH receptor gene expression is also decreased in low-turnover bone, as is observed in high-turnover bone disease. These findings confirm the presence of skeletal resistance to PTH in low-turnover bone accompanying renal failure. Control of calcium, phosphorus, and PTH levels with the target to maintain normal bone turnover is important in maintaining the quality of life of patients on dialysis.

Cerebral venous thrombosis in adult nephrotic syndrome due to systemic amyloidosis.

Although venous thrombosis is one of the common complications in nephrotic patients, cerebral venous thrombosis (CVT) is rarely reported. CVT is so difficult to be detected by conventional diagnostic methods that it is sometimes overlooked despite its potential severity. We report a 79-year-old female with nephrotic syndrome due to systemic amyloidosis who suddenly altered mental status during her hospitalization. The underlying etiology had been not identified by physical examinations, various laboratory data, and repeated computed tomography, and finally she died. The post-mortem examination showed a massive thrombus impacted in intracranial left-sided transverse and sigmoid sinus. This case suggests that CVT can occur in a nephrotic patient who presents unexplained neurological signs and symptoms, which might not be detected only through conventional diagnostic tests.

The effect of angiotensin receptor blockade ARB on the regression of left ventricular hypertrophy in hemodialysis patients: comparison between patients with D allele and non-D allele ACE gene polymorphism.

OBJECTIVE: It is revealed that LVH is one of risk factors for the development of cardiac complications in long-term HD patients. Therefore, maneuvers to reduce hypertrophy of cardium are very important for improving life prognosis. Angiotensin II receptor blockade (ARB) could reduce LVH in general populations without renal failure. However, no conclusive data has been available regarding the clinical consequences of ARB administration on the regression of LVH in HD patients. Furthermore, it has not clearly determined if ACE gene polymorphism has a possible influential effect on it. This study is conducted to clarify these issues. SUBJECTS AND METHOD: 32 hypertensive patients on regular HD (male/female: 21/11, mean age: 60.5 years, mean duration of HD: 52.8 months) were studied. Patients were classified into two groups according to the different type of ACE gene polymorphism: cases with D allele (DD/ID; D group: n = 13) and those without (II; non-D group: n = 19). All patients were administered ARB (losartan 50 - 100 mg/day) and echocardiography (UCG) was performed at 6-month-interval regularly until the end of observation (24 months). RESULTS: Before the commencement of ARB, no differences were found between the two groups, neither in mean blood pressure (MBP: D group/non-D group: 120 +/- 13 vs. 115 +/- 14 mmHg) nor in left ventricular mass index (LVMI: D/non-D: 172 +/- 41 vs. 165 +/- 41 g/m2). During the 24r-month follow-up, there were significant and similar reductions in MBP in both groups. In respect to LVMI, a significant reduction of LVMI was found in the D group after six months (p < 0.01 vs. basal) with a final reduction rate (FRR) -26 +/- 13%, whereas in the non-D group it was found at 24 months (p < 0.01 vs. basal) with FRR -11 +/- 16% (p < 0.01 vs. D group). There were significant differences between the two groups at all points (p < 0.05 at 6, 18 and 24 months, p < 0.005 at 12 months, respectively). CONCLUSION: It is indicated that ARB could insert a regression effect on LVH predominantly in patients with D allele ACE polymorphism, due partly to factor (s) independent of its anti-hypertensive effect.

Maxacalcitol therapy decreases circulating osteoprotegerin levels in dialysis patients with secondary hyperparathyroidism.

BACKGROUND: Osteoprotegerin is a natural glycoprotein which plays a critical role in osteoclast physiology. Elevated levels of circulating osteoprotegerin may account for the development of bone and mineral metabolic abnormalities in uremia. Little is known about the effects of vitamin D therapy on the circulating osteoprotegerin levels in dialysis patients. PATIENTS AND METHODS: Fifty chronic dialysis patients whose plasma intact PTH levels were greater than 300 pg/ml were analyzed for the study. Following a four-week washout time during which all vitamin D administration was halted, 10 microg of maxacalcitol was intravenously injected thrice a week. RESULTS: The circulating intact PTH, bone-specific alkaline phosphatase and intact osteocalcin levels were significantly lowered, while the serum calcium levels were elevated after the therapy. The osteoprotegerin levels significantly decreased after the therapy (p < 0.0001). CONCLUSION: Maxacalcitol therapy reduced the circulating osteoprotegerin levels and improved secondary hyperparathyroidism. The observed effects were the opposite of those expected from previous in vitro studies. Osteoprotegerin may mediate and/or modify the effect of active vitamin D therapy in dialysis patients.

Normalization of reversed bio-intact-PTH(1-84)/intact-PTH ratio after parathyroidectomy in a patient with severe secondary hyperparathyroidism.

The conventional intact-PTH assay detects both (1-84)-PTH and C-terminal fragments. The newer PTH assays, bio-intact-PTH assay and whole-PTH assay, use an antibody that binds only if the first amino acid is present, making it specific for the complete molecule, (1-84)-PTH. Thus, the intact-PTH concentrations are theoretically higher than bio-intact-PTH concentrations, and the ratio of bio-intact-PTH/intact-PTH is usually less than 1. These findings are observed in normal subjects and patients with primary and secondary hyperparathyroidism. Here we present a hemodialysis patient with severe secondary hyperparathyroidism who was found to have abnormally higher plasma bio-intact-PTH concentrations than intact-PTH concentrations, and the abnormally high biointact-PTH/intact-PTH ratio improved after parathyroidectomy (PTx). The patient was a 67-year-old man on maintenance hemodialysis since 1995. Since 2003, he was found to have high plasma intact-PTH concentrations and two swollen parathyroid glands in the neck. PTx with forearm autograft was performed in October 2003. Before PTx, an abnormally high ratio of bio-intact-PTH/intact-PTH was detected (840 pg/ml/770 pg/ml, > 1), while the same ratio was improved to normal range (100 pg/ml/200 pg/ml, < 1). Recently, a few patients with parathyroid carcinoma have been found to have higher (1-84)-PTH concentrations than intact-PTH concentrations with abnormally high (1-84)-PTH/intact-PTH ratio. Moreover, a new molecular form of PTH distinct from (1-84)-PTH was detected in these patients. We speculate that the resected parathyroid gland in our patient might have produced a new molecular form of PTH that was less well detected by the conventional intact-PTH assay.

Role of zinc in regulation of protein tyrosine phosphatase activity in osteoblastic MC3T3-E1 cells: zinc modulation of insulin-like growth factor-I's effect.

Zinc, an essential trace element, has been demonstrated to stimulate bone growth in animal and human. The cellular mechanism by which zinc stimulates bone growth has not been fully clarified. The effect of hormone and zinc on protein tyrosine phosphatase activity in osteoblastic MC3T3-E1 cells was investigated. Cells were cultured for 72 h in medium containing 10% fetal bovine serum (FBS) to obtain subconfluent monolayers, and then exchanged to culture medium containing either vehicle, zinc sulfate or various hormones in the absence of 10% FBS. After medium change, cells were cultured for 48 h. Protein tyrosine phosphatase activity in the lysate of cells was significantly increased by culture with zinc (10(-6) - 10(-4) M). The effect of zinc in increasing the enzyme activity was completely blocked by culture with cycloheximide (10(-7 )M), an inhibitor of protein synthesis, or 5, 6-dichloro-l-beta-D- riboifuranosylbenzimidarzole (DRB) (10(-6) M), an inhibitor of translational activity. Addition of calcium chloride (10 microM) into the reaction mixture caused a significant increase in protein tyrosine phosphatase activity; this increase was completely blocked in the presence of trifluoperazine (50 microM), an antagonist of calmodulin. Culture with zinc caused a significant increase in Ca2+/calmodulin-dependent protein tyrosine phosphatase activity in osteoblastic cells. Protein tyrosine phosphatase activity was significantly raised by culture with parathyroid hormone (human PTH [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]; 10(-7) M), 17beta-estradiol (10(-7) M), insulin-like growth factor-I (IGF-I; 10(-8) M) or insulin (10(-8) M). The enzyme activity was not significantly enhanced by the addition of calcium (10 microM) into the reaction mixture. The effect of PTH or IGF-I in increasing protein tyrosine phosphatase activity was completely blocked by culture with DRB. The IGF-I-induced increase in enzyme activity was significantly enhanced by culture with zinc. Such an effect was not seen in the case of PTH. Moreover, the effect of IGF-I in increasing proliferation of osteoblastic cells was significantly enhanced by culture with zinc. The effect of PTH was not enhanced by zinc. This study demonstrates that protein tyrosine phosphatase activity in osteoblastic cells is enhanced by various bone anabolic factors, and that zinc modulates the effect of IGF-I on protein tyrosine phosphatase activity and cell proliferation.

Percutaneous calcitriol injection therapy (PCIT) for secondary hyperparathyroidism: multicentre trial.

A multicentre trial of percutaneous calcitriol injection therapy (PCIT) was designed to evaluate its clinical usefulness. During a 12-week period, measurement of intact PTH concentration, and other parameters, and ultrasonography were carried out in conjunction with PCIT in 19 haemodialysis patients with secondary hyperparathyroidism and enlarged parathyroid glands (PTGs) that were resistant to vitamin D pulse therapy. Calcijex was injected directly into the PTG three times per week on the patient's non-dialysis days: eight patients received a 2 microg/ml preparation (group A) and 12 received 1 microg/ml (group B). A strong clinical effect was observed in group A compared with group B, which suggests that the effect of calcitriol by direct injection is stronger when there is a higher concentration of calcitriol in the PTG. In group B, the cases with an initial intact PTH concentration <1000 pg/ml and a single enlarged PTG had a good response to the treatment. Concentrations of calcium and phosphate were not significantly changed in either group. All cases had decreased blood flow in the PTG after three episodes of PCIT and, although the size of the PTG was unchanged, or even a little increased, immediately after the treatment, it decreased gradually over 2-6 weeks. PCIT may be effective for comparatively slight secondary hyperparathyroidism, but further investigation is necessary because there were comparatively few cases.