Involvement of α-klotho in growth hormone (GH) signaling.

Growth hormone (GH) exerts multiple effects on different organs directly or via its main mediator, insulin-like growth factor1 (IGF1). In this study, we focused on the novel relationship between GH action and the antiaging hormone α-klotho. Immunofluorescent staining of α-klotho was observed in the renal distal tubules and pituitary glands of somatostatin- and GH-positive cells in wild-type (WT) mice. Treatment of 4-week-old WT mice with GH increased IGF1 mRNA expression in the pituitary gland, liver, heart, kidney, and bone but increased α-klotho mRNA expression only in the pituitary gland, kidney, and bone. Increased α-klotho protein levels were observed in the kidney but not in the pituitary gland. No induction of α-klotho RNA expression by GH was observed in juvenile mice with kidney disease, indicating GH resistance. Furthermore, GH and α-klotho supplementation in HEK293 cells transfected with GHR increased Janus kinase 2 mRNA (a GH downstream signal) expression compared to supplementation with GH alone. In conclusion, we suggest that 1) the kidney is the main source of secreted α-klotho, which is detected in blood by the downstream action of GH, 2) α-klotho induction by GH is resistant in kidney disease, and 3) α-klotho might be an enhanced regulator of GH signaling.

Pre-Transplant Calcimimetic Use and Dose Information Improves the Accuracy of Prediction of Tertiary Hyperparathyroidism after Kidney Transplantation: A Retrospective Cohort Study.

Tertiary hyperparathyroidism (THPT) is characterized by elevated parathyroid hormone and serum calcium levels after kidney transplantation (KTx). To ascertain whether pre-transplant calcimimetic use and dose information would improve THPT prediction accuracy, this retrospective cohort study evaluated patients who underwent KTx between 2010 and 2022. The primary outcome was the development of clinically relevant THPT. Logistic regression analysis was used to evaluate pre-transplant calcimimetic use as a determinant of THPT development. Participants were categorized into four groups according to calcimimetic dose, developing two THPT prediction models (with or without calcimimetic information). Continuous net reclassification improvement (CNRI) and integrated discrimination improvement (IDI) were calculated to assess ability to reclassify the degree of THPT risk by adding pre-transplant calcimimetic information. Of the 554 patients, 87 (15.7%) developed THPT, whereas 139 (25.1%) received pre-transplant calcimimetic treatment. Multivariate logistic regression analysis revealed that pre-transplant calcimimetic use was significantly associated with THPT development. Pre-transplant calcimimetic information significantly improved the predicted probability accuracy of THPT (CNRI and IDI were 0.91 [p < 0.001], and 0.09 [p < 0.001], respectively). The THPT prediction model including pre-transplant calcimimetic information as a predictive factor can contribute to the prevention and early treatment of THPT in the era of calcimimetics.

Persistent hyperparathyroidism after preemptive kidney transplantation.

BACKGROUND: Long-term dialysis vintage is a predictor of persistent hyperparathyroidism (HPT) after kidney transplantation (KTx). Recently, preemptive kidney transplantation (PKT) has increased. However, the incidence, predictors, and clinical implications of HPT after PKT are unclear. Here, we aimed to elucidate these considerations. METHODS: In this retrospective cohort study, we enrolled patients who underwent PKT between 2000 and 2016. Those who lost their graft within 1 year posttransplant were excluded. HPT was defined as an intact parathyroid hormone (PTH) level exceeding 80 pg/mL or hypercalcemia unexplained by causes other than HPT. Patients were divided into two groups based on the presence of HPT 1 year after PKT. The primary outcome was the predictors of HPT after PKT, and the secondary outcome was graft survival. RESULTS: Among the 340 consecutive patients who underwent PKT, 188 did not have HPT (HPT-free group) and 152 had HPT (HPT group). Multivariate logistic regression analysis revealed that pretransplant PTH level (P < 0.001; odds ratio [OR], 5.480; 95% confidence interval [CI], 2.070-14.50) and preoperative donor-estimated glomerular filtration rate (P = 0.033; OR, 0.978; 95% CI, 0.957-0.998) were independent predictors of HPT after PKT. Death-censored graft survival was significantly lower in the HPT group than that in the HPT-free group (90.4% vs. 96.4% at 10 years, P = 0.009). CONCLUSIONS: Pretransplant PTH levels and donor kidney function were independent predictors of HPT after PKT. In addition, HPT was associated with worse graft outcomes even after PKT.

Possible Advantage of Glucagon-Like Peptide 1 Receptor Agonists for Kidney Transplant Recipients With Type 2 Diabetes.

CONTEXT: Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have the potential to improve native kidney function. OBJECTIVE: This work aimed to elucidate the possible protective effects of GLP-1 RAs on kidney graft function after successful kidney transplantation (KTX). METHODS: This retrospective cohort study included all KTX recipients (KTRs) at our facility with type 2 diabetes who were followed up from 1 month post-transplantation for 24 months or longer as of December 31, 2020. We investigated associations between the use of GLP-1 RAs and other antidiabetic medications (non-GLP-1 RAs) and the risk of sustained estimated glomerular filtration rate (eGFR) reduction (40% reduction compared with baseline for 4 months) for KTRs with type 2 diabetes. We calculated the propensity score of initiating GLP-1 RAs compared with that of initiating non-GLP-1 RAs as a function of baseline covariates using logistic regression. The inverse probability of the treatment-weighted odds ratio was estimated to control for baseline confounding variables. Sodium-glucose cotransporter 2 inhibitor use was a competing event. The primary outcome was sustained eGFR reduction of at least 40% from baseline for 4 months post-transplantation. RESULTS: Seventy-three patients were GLP-1 RA users and 73 were non-GLP-1 RA users. Six patients and 1 patient in the non-GLP-1 RA and GLP-1 RA groups had sustained eGFR reduction. GLP-1 RA use after KTX was associated with a lower risk of sustained eGFR reduction. CONCLUSION: GLP-1 RAs resulted in lower eGFR reduction compared with non-GLP-1 RAs and may contribute to better kidney graft survival after KTX.

Elevated parathyroid hormone one year after kidney transplantation is an independent risk factor for graft loss even without hypercalcemia.

BACKGROUND: Hypercalcemic hyperparathyroidism has been associated with poor outcomes after kidney transplantation (KTx). However, the clinical implications of normocalcemic hyperparathyroidism after KTx are unclear. This retrospective cohort study attempted to identify these implications. METHODS: Normocalcemic recipients who underwent KTx between 2000 and 2016 without a history of parathyroidectomy were included in the study. Those who lost their graft within 1 year posttransplant were excluded. Normocalcemia was defined as total serum calcium levels of 8.5-10.5 mg/dL, while hyperparathyroidism was defined as when intact parathyroid hormone levels exceeded 80 pg/mL. The patients were divided into two groups based on the presence of hyperparathyroidism 1 year after KTx. The primary outcome was the risk of graft loss. RESULTS: Among the 892 consecutive patients, 493 did not have hyperparathyroidism (HPT-free group), and 399 had normocalcemic hyperparathyroidism (NC-HPT group). Ninety-five patients lost their grafts. Death-censored graft survival after KTx was significantly lower in the NC-HPT group than in the HPT-free group (96.7% vs. 99.6% after 5 years, respectively, P < 0.001). Cox hazard analysis revealed that normocalcemic hyperparathyroidism was an independent risk factor for graft loss (P = 0.002; hazard ratio, 1.94; 95% confidence interval, 1.27-2.98). CONCLUSIONS: Normocalcemic hyperparathyroidism 1 year after KTx was an independent risk factor for death-censored graft loss. Early intervention of elevated parathyroid hormone levels may lead to better graft outcomes, even without overt hypercalcemia.

Predictors of Bone Mineral Density Improvement after Parathyroidectomy for Secondary Hyperparathyroidism: A Retrospective Single-Center Analysis.

BACKGROUND: Parathyroidectomy (PTx) reportedly increases bone mineral density (BMD) in patients with severe secondary hyperparathyroidism (SHPT). To date, however, there has not been sufficient evidence on predictors of BMD improvement post-PTx for SHPT, an issue the present retrospective cohort study aimed to address. METHODS: A total of 173 SHPT patients who underwent total PTx with forearm autograft between 2009 and 2017 were included in the present study. Demographic information, perioperative laboratory data and pre- and post-PTx BMD values (measured by dual-energy X-ray absorptiometry) were collected from their medical records. The change in BMD post-PTx in the lumbar spine was evaluated as the primary outcome. Then, a multivariate logistic regression analysis was performed for a ≥ 10% increase in BMD post-PTx. RESULTS: Overall, the median BMD in the lumbar spine was increased by 8.7% post-PTx. The multivariate logistic regression analysis revealed that age ≥ 70 years (P = 0.005; odds ratio [OR], 0.138; 95% confidence interval [CI]: 0.034-0.555), serum Ca level (P = 0.017; OR, 0.598; 95% CI: 0.392-0.911) and pre-PTx BMD in the lumbar spine (P = 0.003; OR, 0.013; 95% CI: 0.001-0.229) were negatively associated with a ≥ 10% increase in BMD post-PTx. CONCLUSION: Our study demonstrated that presurgical age, serum Ca levels and BMD values could better predict an improvement in BMD post-PTx in SHPT patients.

Comparison of Pre- and Post-transplant Parathyroidectomy in Renal Transplant Recipients and the Impact of Parathyroidectomy Timing on Calcium Metabolism and Renal Allograft Function: A Retrospective Single-Center Analysis.

BACKGROUND: The effect of parathyroidectomy (PTx) timing on serum calcium (Ca) levels and renal functions in renal transplant recipients with severe hyperparathyroidism (HPT) remains unclear. We retrospectively aimed to investigate and compare the clinical data of patients who underwent pre- and post-transplant PTx and elucidated the impact of PTx timing on serum Ca levels and renal graft outcomes after renal transplantation (RTx). METHODS: During January 2000-December 2016, 53 and 55 patients underwent post-transplant PTx (Post-RTx group) and pretransplant PTx (Pre-RTx group), respectively. The serum Ca levels and estimated glomerular filtration rate (eGFR) were assessed in both groups. RESULTS: At the end of the follow-up, the serum Ca levels were significantly higher and the incidence of hypocalcemia was significantly lower in the Pre-RTx group than in the Post-RTx group [9.5 vs. 8.9 mg/dL, P < 0.001; 14.5% vs. 34.0%, P = 0.024]. The decrease in the eGFR 12-36 months after RTx was more significant in the Post-RTx group than in the Pre-RTx group (-13.8% vs. -0.9%; P = 0.001). A logistic regression involving age, sex, dialysis period, and serum parathormone level revealed that post-transplant PTx is an independent risk factor for persistent hypocalcemia at the end of the follow-up (P = 0.034) and for a >20% decrease in the eGFR 12-36 months after RTx (P = 0.029). CONCLUSIONS: In renal transplant candidates with severe HPT, pretransplant PTx should be considered to prevent persistent hypocalcemia and deterioration of the renal graft function.

Disrupted tubular parathyroid hormone/parathyroid hormone receptor signaling and damaged tubular cell viability possibly trigger postsurgical kidney injury in patients with advanced hyperparathyroidism.

BACKGROUND: Parathyroidectomy (PTX) that alleviates clinical manifestations of advanced hyperparathyroidism, including hypercalcemia and hypophosphatemia, is considered the best protection from calcium overload in the kidney. However, little is known about the relationship between postsurgical robust parathyroid hormone (PTH) reduction and perisurgical renal tubular cell viability. Post-PTX kidney function is still a crucial issue for primary hyperparathyroidism (PHPT) and tertiary hyperparathyroidism after kidney transplantation (THPT). METHODS: As a clinical study, we examined data from 52 consecutive patients (45 with PHPT, 7 with THPT) who underwent PTX in our center between 2015 and 2017 to identify post-PTX kidney injury. Their clinical data, including urinary liver-type fatty acid-binding protein (L-FABP), a tubular biomarker for acute kidney injury (AKI), were obtained from patient charts. An absolute change in serum creatinine level of 0.3 mg/dL (26.5 µmol/L) on Day 2 after PTX defines AKI. Post-PTX calcium supplement dose adjustment was performed to strictly maintain serum calcium at the lower half of the normal range. To mimic post-PTX-related kidney status, a unique parathyroidectomized rat model was produced as follows: 13-week-old rats underwent thyroparathyroidectomy (TPTX) and/or 5/6 subtotal nephrectomy (NX). Indicated TPTX rats were given continuous infusion of a physiological level of 1-34 PTH using a subcutaneously implanted osmotic minipump. Immunofluorescence analyses were performed by polyclonal antibodies against PTH receptor (PTHR) and a possible key modulator of kidney injury, Klotho. RESULTS: Patients' estimated glomerular filtration rate (eGFR) did not have any clinically relevant change (62.5 ± 22.0 versus 59.4 ± 21.9 mL/min/1.73 m2, NS), whereas serum calcium (2.7 ± 0.18 versus 2.2 ± 0.16 mmol/L, P < 0.0001) and phosphorus levels (0.87 ± 0.19 versus 1.1 ± 0.23 mmol/L, P < 0.0001) were normalized and PTH decreased robustly (181 ± 99.1 versus 23.7 ± 16.8 pg/mL, P < 0.0001) after successful PTX. However, six patients who met postsurgical AKI criteria had lower eGFR and greater L-FABP than those without AKI. Receiver operating characteristics (ROC) analysis revealed eGFR <35 mL/min/1.73 m2 had 83% accuracy. Strikingly, L-FABP >9.8 µg/g creatinine had 100% accuracy in predicting post-PTX-related AKI. Rat kidney PTHR expression was lower in TPTX. PTH infusion (+PTH) restored tubular PTHR expression in rats that underwent TPTX. Rats with TPTX, +PTH and 5/6 NX had decreased PTHR expression compared with those without 5/6 NX. 5/6 NX partially cancelled tubular PTHR upregulation driven by +PTH. Tubular Klotho was modestly expressed in normal rat kidneys, whereas enhanced patchy tubular expression was identified in 5/6 NX rat kidneys. This Klotho and expression and localization pattern was absolutely canceled in TPTX, suggesting that PTH indirectly modulated the Klotho expression pattern. TPTX +PTH recovered tubular Klotho expression and even triggered diffusely abundant Klotho expression. 5/6 NX decreased viable tubular cells and eventually downregulated tubular Klotho expression and localization. CONCLUSIONS: Preexisting tubular damage is a potential risk factor for AKI after PTX although, overall patients with hyperparathyroidism are expected to keep favorable kidney function after PTX. Patients with elevated tubular cell biomarker levels may suffer post-PTX kidney impairment even though calcium supplement is meticulously adjusted after PTX. Our unique experimental rat model suggests that blunted tubular PTH/PTHR signaling may damage tubular cell viability and deteriorate kidney function through a Klotho-linked pathway.

Semiquantitative analysis of virtual histology derived from intravascular ultrasound images at vascular access stenosis.

Vascular access failure, such as recurrent stenosis and thrombosis, is a major concern in patients with end-stage kidney disease. Neointimal hyperplasia development at the anastomosis site of outflow vessels is a primal cause for recurrent vascular access failure. We previously shed some lights into a role of vitamin D, which exerts a protective effect against neointimal hyperplasia formation. Virtual histology, derived from intravascular ultrasound technology, provides novel insights into plaque composition analysis in atherosclerotic diseases. However, there is so far a lack of evidence on the relation between virtual histology and pathophysiological findings. To elucidate this missing link, we comprehensively reviewed 10 chronic hemodialysis patients who underwent repeated intravascular ultrasound-guided balloon angioplasty. Their age, dialysis vintage, and follow-up period were 75.0 ± 4.24, 20.5 ± 2.12, and 11.5 ± 0.71 (mean ± standard deviation) years, respectively. Pathological cross-sectional analyses were performed using specimens from vascular access surgeries during the follow-up period. Interestingly, positive relation is found between virtual histology-constructed fibrous tissue and pathological neointimal hyperplasia. Strikingly, immunohistological analysis revealed that vitamin D receptor-positive myofibroblasts were abundantly distributed in the equivalent area to virtual histology fibrous tissue. Our 10-year follow-up data of resistant vascular access stenosis indicates strong correlation between vitamin D receptor-rich neointimal vessel hypertrophy and intravascular ultrasound-assisted virtual histological analysis. Intravascular ultrasound technology is one of the minimally invasive diagnostic tools to provide histologically relevant tissue structure information and help determine target vessel stenosis on vascular access.

The Pituitary Is a Candidate Organ That Modulates Circulating Klotho Levels.

CONTEXT: The antiaging protein Klotho is shed and released into the blood stream (soluble Klotho). Growth hormone (GH) is considered an active Klotho regulator, because growth retardation is described in Klotho-deficient mice. The origin of circulating Klotho is, however, not fully understood. OBJECTIVES: Our objective was to analyze a possible role of the pituitary in regulating soluble Klotho in patients with pituitary adenomas. PATIENTS DESIGN AND SETTING: We analyzed serum levels of soluble Klotho, GH, and insulin-like growth factor 1 (IGF-1) from 21 consecutive patients in our center with pituitary tumor, 7 with GH-producing adenomas (GHomas), and 14 with non-GH-producing pituitary adenomas (non-GHomas), before and after endoscopic transsphenoidal surgery (eTSS). MAIN OUTCOME MEASURE: Soluble Klotho levels were determined by ELISA with antihuman Klotho antibodies. RESULTS: Baseline soluble Klotho levels in all patients, those with GHoma and those with non-GHoma, were 542 (median) (interquartile range: 403, 652), 1083 (425, 1213), and 525 (399, 590), respectively. A drastic reduction in Klotho levels was identified in those with GHoma, accompanied by decreases in GH and IGF-1 levels, after eTSS. Interestingly, patients with non-GHoma had significant declines in soluble Klotho without any significant changes in GH levels. Moreover, an oral glucose tolerance test revealed that soluble Klotho levels decreased, whereas a paradoxical GH peak was observed after glucose intake in a patient with GHoma. CONCLUSIONS: Our data suggest that the pituitary may be a key organ that regulates circulating Klotho concentrations, implying that the pituitary possibly controls circulating Klotho through GH-dependent and/or GH-independent mechanisms.

A case series of favorable vessel dilatation using a nitinol scoring element-equipped helical balloon catheter (AngioSculpt®).

OBJECTIVE: Although percutaneous transluminal angioplasty is an effective therapy against vascular access failure in hemodialysis patients, recurrent stenosis imposes enormous burden for hemodialysis patients. A nitinol scoring element-equipped helical balloon catheter (AngioSculpt®) has been altered the landscape for treating several vascular diseases. It is not, however, fully elucidated whether AngioSculpt for advanced vascular access stenosis, difficult to expand by conventional balloons, successfully provides bailout angioplasty. Here, we report our cases whose intradialytic venous pressure significantly improved after percutaneous transluminal angioplasty without any serious adverse complications using AngioSculpt. PATIENTS AND METHODS: Among patients undergoing hemodialysis in Masuko Memorial Hospital, 16 cases with resistant and recurrent vascular access stenosis underwent AngioSculpt (diameter 6 mm, total length 4 cm) angioplasty. We simultaneously measured the average venous pressures during hemodialysis before and after percutaneous transluminal angioplasty. RESULTS: The average outflow vessel stenosis rate was 73.0 ± 11.3% before AngioSculpt intervention. Fully enlarged vessels were observed by expanding vessels at maximum pressure of 14 atm in all cases without any complications including vascular ruptures. Their intradialytic venous pressures decreased from 181.8 ± 39.2 mmHg to 150.5 ± 39.3 mmHg ( p < 0.0001). CONCLUSION: AngioSculpt may provide a promising option for treating hemodialysis patients with severely advanced vascular access stenosis, who would otherwise need repeated vascular access surgeries and/or conventional percutaneous transluminal angioplasties.

An efficacy of intensive vitamin D delivery to neointimal hyperplasia in recurrent vascular access stenosis.

PURPOSE: Neointimal hyperplasia (NH) causes vascular access (VA) stenosis, which results in serious under-dialytic morbidity in hemodialysis patients. We sought to assess whether a vitamin D intervention to NH lesions leads to better VA patency and examined clinical and in vitro studies. METHODS: A pilot clinical study of six hemodialysis patients was conducted to elucidate whether 0.5 µg calcitriol injection to stenotic lesion after balloon angioplasty (PTA) maintains better vessel patency until the next follow-up angiography. Localized vitamin D exposure was utilized by delivering and fixing calcitriol intensively at the stenotic lesion through a side-hole catheter with balloon clamping. We also performed vascular smooth muscle cell (VSMC) culture to detect both apoptosis (cell death detection assay) and cell viability (5-Bromo-2'-deoxy-uridine incorporation), and explored the efficacy of vitamin D to inhibit VSMC proliferation. Additionally, immunohistochemistry (IHC) was conducted to examine vitamin D receptor (VDR) expression at NH lesion, obtained from VA surgery. RESULTS: Percent patency, the proportion between stenotic and non-stenotic vessel diameters, increased significantly (p = 0.03) after directly catheter-delivered 0.5 µg calcitriol administration. In vitro VSMC studies, 0.1 nM calcitriol significantly (p<0.05) enhanced apoptosis and cell-cycle inhibition for two different calcitriol exposure times (15 minutes and 24 hours). IHC staining revealed that VDR-positive hyperplastic cells were observed at NH lesion. CONCLUSIONS: Intensive vitamin D exposure at NH lesion has an ability to inhibit further VSMC proliferation, and presumably leads to greater patency rate for recurrent VA stenosis. Further studies are needed to clarify whether its unique property is exhibited through VDR-mediated mechanism.

Role of multifunctional cell cycle modulators in advanced secondary hyperparathyroidism.

Long-term dialysis for patients with end stage renal disease leads to an unavoidable common complication, which is secondary hyperparathyroidism. Two histological patterns (nodular and diffuse hyperplasia) are detected, indicating that continuous uremia-related stimulation promotes parathyroid cell proliferation from diffuse to nodular growth. However, the key molecular mechanism is not fully understood, which narrows the range of therapeutic options for advanced secondary hyperparathyroidism. To address this issue, we utilized surgically resected normal and hyperplastic parathyroid glands to perform immunohistochemical analysis of a multifunctional cell cycle modulator, CCAAT enhancer binding protein (C/EBP)ß. In contrast to normal parathyroid tissue and diffuse hyperplasia, the intensity of C/EBPß staining was homogeneously increased in the parathyroid cells from nodules, along with a higher cyclin D1 labeling index (108.0 ± 19.5, mean ± SEM) and Ki-67 labeling index (31.70 ± 0.49). Normal and diffuse hyperplastic parathyroid glands had far fewer cyclin D1- and Ki-67-positive cells (P < 0.001). Immunofluorescent double staining showed abundant coexpression of Th235 (mitogen-activated protein kinase [MAPK] phosphorylation site) C/EBPß, along with upregulation of cytoplasmic Ras in nodular hyperplasia. In conclusion, hyperplastic parathyroid cells in nodules have an autonomous proliferation mechanism similar to that of cancer, in which C/EBPß is upregulated and phosphorylated to interact with the oncogenic Ras/MAPK pathway. C/EBPß may be a novel target molecule for blocking the growth circuit that underlies parathyroid tumorigenesis in secondary hyperparathyroidism.

A case of acute rejection with adenovirus infection after ABO-incompatible kidney transplantation.

We report clinical and histopathologic findings of a case of acute rejection with adenovirus infection after kidney transplantation. A 63-yr-old woman with end-stage renal disease caused by lupus nephritis received an ABO-incompatible living kidney transplantation from her husband. On the 7th post-operative day (POD), she had fever, hematuria, and bladder irritation. Although she was treated with an antibiotic, the symptoms were not improved. We diagnosed adenovirus infection as positive with the urine shell vial method and blood PCR analysis. Cyclophosphamide was interrupted and immunoglobulin therapy was performed. However, urine output decreased and serum creatinine levels increased. An episode biopsy was performed on POD 20. We diagnosed acute antibody-mediated rejection. She was treated with plasma exchange for acute rejection and antiviral drug (rivabirin) for active adenovirus infection. However, the renal graft dysfunction was deemed irreversible and the renal graft was removed on POD 34. The graftectomy specimen showed acute rejection and acute tubular necrosis with adenovirus infection.

1,25-dihydroxyvitamin D synthesis after renal transplantation: the role of fibroblast growth factor 23 and cyclosporine.

1,25-dihydroxyvitamin D(3) (1,25D) is tightly regulated by circulating factors, containing fibroblast growth factor 23 (FGF23). However, this control is disturbed in chronic kidney disease. Renal transplantation (RTX) alters 1,25D homeostasis. To examine the clinical relevance of 1,25D in RTX, we drew blood samples from 27 renal transplant recipients (20 cyclosporine-based, seven non-cyclosporine-based) and examined serum concentrations of 25-hydroxyvitamin D(3) (25D), 1,25D, and FGF23. Our protocol for cyclosporine was as follows, an initial dose of 8 mg/kg two d before RTX, and subsequently adjusted on the basis of the pharmacokinetic profile. No baseline differences were observed between cyclosporine-based and non-cyclosporine-based regimens before RTX. All variables except 1,25D levels changed similarly between the two groups. In the cyclosporine-based regimen, 1,25D levels increased steeply on day 2 and re-increased from days 7 to 21. Post-transplant FGF23 levels sharply decreased until day 14. Interestingly, the cyclosporine-treated group revealed an unexpected tendency between circulating 1,25D and FGF23 on day 21. Multiple regression analyses indicated the cyclosporine pharmacokinetic profile as a significant predictor for 1,25D levels. Post-transplant 1,25D production is induced by a steep fall in serum FGF23 and prompt graft function on day 2; 1,25D levels thereafter may be stimulated by circulating abundant cyclosporine.

Restored cardiac conditions and left ventricular function after parathyroidectomy in a hemodialysis patient. Parathyroidectomy improves cardiac fatty acid metabolism assessed by 123I-BMIPP.

A 62 year-old female hemodialysis patient underwent parathyroidectomy to treat secondary hyperparathyroidism. On the preoperative assessment, the plasma levels of parathyroid hormone (PTH) and B-type natriuretic peptide (BNP) were elevated. Echocardiography showed reduced left ventricular (LV) contraction. Myocardial iodine-123-15-(p-iodophenyl)-3-(R,S) methylpentadecanoic acid ((123)I-BMIPP) scintigraphy showed moderately reduced tracer uptake in the postero-inferior area on single-photon emission computed tomography and decreased washout on the planar images. After parathyroidectomy, the plasma levels of PTH and BNP decreased, followed by improvement in LV contraction. Myocardial (123)I-BMIPP scintigraphy revealed that the washout on planar images had increased, which suggests that myocardial (123)I-BMIPP scintigraphy is useful for estimating the effect of parathyroidectomy on cardiac function.

Parathyroidectomy for secondary hyperparathyroidism in the era of calcimimetics.

Secondary hyperparathyroidism (SHPT) is one of the major complications experienced by patients with renal failure. Cinacalcet hydrochloride, a calcimimetic, is a new modality for the treatment of SHPT and is able to suppress a high parathyroid hormone level remarkably well. However, for patients with uncontrollable SHPT while on cinacalcet, those with severe SHPT symptoms and those with difficulty being treated with cinacalcet because of side-effects, parathyroidectomy (PTx) may be indicated as usual. PTx can induce a remarkable improvement in SHPT: postoperative serum phosphorus and calcium levels are easily maintained within their target ranges, quality of life is improved, survival rates are improved and the procedure has high cost-effectiveness, so for the patients with SHPT refractory to conventional vitamin D or vitamin D analog treatment in whom long-term survival is expected, PTx might be a more preferable treatment. On the other hand, cinacalcet is the first choice for patients in whom it is difficult to manage SHPT with PTx. Indications are patients (i) for whom surgery under general anesthesia would be highly invasive; (ii) whose parathyroid glands are located in an area making resection difficult; (iii) in whom the affected parathyroid tissues are difficult to identify; (iv) in whom it is difficult to resect all affected parathyroid tissues; and (v) who have undergone repeated surgery or percutaneous ethanol injection therapy and may develop serious complications such as bilateral recurrent laryngeal nerve paralysis. Cinacalcet may be a rescuer treatment for these patients.

Modified laparoscopic splenectomy: a beneficial technique for ABO-incompatible living donor renal transplantation candidates on hemodialysis.

Advances in laparoscopy have enabled minimally invasive surgical treatment of splenic diseases. Even with these advances, laparoscopic splenectomy in patients on dialysis can be difficult because of tissue fragility due to the underlying renal disease. We report a safe surgical technique for laparoscopic splenectomy in patients on maintenance dialysis that is suitable for use before ABO-incompatible living donor renal transplantation (LDRTx). Between June 1972 and December 2006, a total of 800 patients underwent LDRTx in our department, including 82 patients who underwent ABO-incompatible LDRTx. Between April 2001 and December 2006 we performed laparoscopic splenectomy in 48 hemodialysis patients as a pretreatment before ABO-incompatible LDRTx. Under general anesthesia the operation was performed using a new technique, referred to as the "splenic hilum lump method." We evaluated the surgical outcomes, such as the operative time, amount of blood loss, efficacy, and complications. The mean operative time was 131.6 +/- 38.4 min and mean blood loss was 126 +/- 395 mL. Blood transfusion was required in three patients. All cases had satisfactory kidney function after LDRTx and none developed kidney graft failure due to acute rejection. Almost all patients could walk the day after laparoscopic splenectomy and were satisfied with the cosmetic appearance of the scar after wound healing. The surgical technique we report here can be safely performed on patients with renal failure who require caution because of tissue fragility. Laparoscopic splenectomy is a safe, effective and less invasive operative procedure as a pretreatment for ABO-incompatible LDRTx.

Relationship between the dimension of parathyroid glands estimated by ultrasonography and the hyperplastic pattern in patients with renal hyperparathyroidism.

In renal hyperparathyroidism (HPT), the parathyroid glands initially proliferate diffusely and polyclonally, and are then transformed to monoclonal nodular hyperplasia with aggressive growth potential. In this study we evaluated the relationship between the maximal dimension of parathyroid glands estimated by ultrasonography (US) and the hyperplastic pattern of parathyroid glands in patients with renal HPT. Between October 1999 and December 2006, 141 patients who underwent total parathyroidectomy (PTx) with forearm autograft in our department were enrolled in this study. In these patients 308 parathyroid glands were detected by US before PTx. The largest dimension of the gland estimated preoperatively by US was correlated closely with its measurement at surgery (R2 was 0.31, P < 0.001). The maximal dimension of diffuse hyperplastic glands was significantly smaller than that of the glands with nodular hyperplastic glands (P < 0.001). There was a strong correlation between the pattern of parathyroid hyperplasia and the glandular diameter when we defined 8 mm as the maximal diameter estimated by US as a cut-off value. As a result of receiver operating characteristic analyses, using these criteria the US technique could predict nodular hyperplasia with a high sensitivity (78.9%) and specificity (78.7%). Parathyroid glands that are enlarged by more than 8 mm in the largest dimension estimated by US may represent glands with nodular hyperplasia.

Incidence of parathyroid glands located in thymus in patients with renal hyperparathyroidism.

BACKGROUND: Parathyroid glands are frequently located in thymus, and it is essential to resect thymic tissue from the neck incision, especially in surgery for renal hyperparathyroidism (HPT). METHODS: In this study, we evaluated the incidence, location, and type of intrathymic parathyroid glands in 902 patients who underwent initial parathyroidectomy (PTx) for advanced renal HPT in our department. Removal of the thymic tongues on both sides was routinely performed from the neck incision, and the thymic tissue was carefully examined both macroscopically and microscopically. RESULTS: Of the 902 patients in the study, 269 had only inferior parathyroid glands in the thymus, in 62 patients only supernumerary glands were found in the thymic tongue, and in 78 patients both inferior and supernumerary glands were present in thymic tissue. Therefore the incidence of patients with intrathymic glands was 45.3% (269 + 62 + 78 = 409/902). In 129 (92.1%) of 140 patients with supernumerary glands in the thymic tongue, these glands were detected only on histopathological examination, and about half of them were classified as the parathyromatosis type. CONCLUSIONS: In the human, parathyroid glands might be located in the thymus in about 50%. If the inferior gland/glands cannot be found around the inferior pole of thyroid lobe, it is very important to search for glands in the thymic tongue. Moreover, to avoid missing supernumerary glands, removal of the thymic tongue on both sides is essential in surgery for renal HPT.