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.

Cinacalcet hydrochloride relieves hypercalcemia in Japanese patients with parathyroid cancer and intractable primary hyperparathyroidism.

Pharmacological treatment of hypercalcemia is essential for patients with parathyroid carcinoma and intractable primary hyperparathyroidism (PHPT). Use of the calcimimetic cinacalcet hydrochloride (cinacalcet) is an option to treat such patients. We investigated the efficacy and safety of cinacalcet in Japanese patients with parathyroid carcinoma and intractable PHPT. Five Japanese patients with parathyroid carcinoma and two with intractable PHPT were enrolled in an open-label, single-arm study consisting of titration and maintenance phases. Cinacalcet doses were titrated until the albumin-corrected serum calcium concentration decreased to 10.0 mg/dL or less or until dose escalation was considered not necessary or feasible. Serum calcium concentration at the baseline was 12.1 ± 1.3 mg/dL (mean ± standard deviation; range 10.4-14.6 mg/dL) and decreased to 10.1 ± 1.6 mg/dL (range 8.6-13.3 mg/dL) at the end of the titration phase with cinacalcet at a dosage of up to 75 mg three times a day. At the end of the titration phase, at least a 1 mg/dL reduction in serum calcium concentration from the baseline was observed in five patients (three with carcinoma and two with PHPT), and it decreased to the normocalcemic range in five patients (three with carcinoma and two with PHPT). Common adverse events were nausea and vomiting. One patient discontinued participation in the study because of an adverse event, liver disorder. Cinacalcet effectively relieved hypercalcemia in 60% of the Japanese patients with parathyroid carcinoma and might be effective in those with intractable PHPT. The drug might be tolerable and safe at a dosage of at most 75 mg three times a day.

Beneficial effects of preemptive kidney transplantation on calcium and phosphorus disorders in early post-transplant recipients.

BACKGROUND: Recently, preemptive kidney transplantation (PKT) has increased in Japan; however, the effects of PKT on calcium (Ca) and phosphorus (Pi) metabolism are poorly understood. METHODS: Thirty-two consecutive patients were enrolled in this study at Nagoya Daini Red Cross Hospital. Fifteen patients were in the PKT group and 17 patients were in the non-PKT group. Parameters of Ca and Pi metabolism, including fibroblast growth factor (FGF) 23 and intact parathyroid hormone, were measured before transplantation and 1, 3, and 24 weeks after transplantation. RESULTS: FGF 23 decreased dramatically in both groups after transplantation; however, FGF 23 before transplantation and at 1 and 3 weeks after transplantation was significantly lower in the PKT group than in the non-PKT group (p < 0.05). Although iPTH levels were higher in the PKT group than in the non-PKT group before transplantation, these levels were lower in the PKT group at 24 weeks after transplantation (p < 0.05). Corrected Ca was lower at 24 weeks in the PKT group (p < 0.05), whereas Pi was lower in the non-PKT group at 1 and 3 weeks (p < 0.05), but not significantly different at 24 weeks. Multivariate linear regression analysis revealed that FGF 23 before transplantation was the strongest predictor of Ca and Pi disorders in early post-transplant recipients. CONCLUSIONS: This study suggests that PKT has beneficial effects on Ca and Pi metabolism and pre-transplant FGF 23 levels are a good marker of post-transplant Ca and Pi metabolism disorders.

Impact of lanthanum carbonate on cortical bone in dialysis patients with adynamic bone disease.

Among the most serious problems in patients with chronic kidney disease (CKD) is fragility of cortical bone caused by cortical thinning and increased cortical porosity; the cortical fragility is sometimes irreversible, with fractures generally initiating from cortical bone. Therefore, development of treatments for problems of cortical bone is urgently desired. Cortical bone has the three surfaces, including the periosteal surface, intracortical spaces and endocortical surface. Bone turnover at the endocortical surface and intracortical resorption spaces are increased as compared with that at cancellous surface. Bone growth sometimes depends on apposition at the periosteal surface. We treated hyperphosphatemia in two hemodialysis patients with adynamic bone disease with 750-1500 mg/day of lanthanum carbonate, which is a non-calcium containing phosphate binder; the treatment resulted in a decrease of the serum phosphorus levels (P levels), without significant change of the serum intact parathyroid hormone levels. We now report that treatment of these patients with lanthanum carbonate increased mineralization of the periosteal surface, increased bone mass within the intracortical resorption spaces and increased mineralization of the minimodeling surface at the endocortical surface. In addition, woven bone volume in cortical bone was decreased and mineralization of bone units, namely, osteons, was increased. Although these findings were not observed across all surfaces of the cortical bone in the patients, it is expected that lanthanum carbonate would increase the cortical stability in CKD patients, with consequent reduction in the fracture rate in these patients.

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.

Effects of serum calcium, phosphorous, and intact parathyroid hormone levels on survival in chronic hemodialysis patients in Japan.

Disturbances in bone mineral metabolism are common in chronic hemodialysis (HD) patients and often underlie morbid conditions and mortality; however, no large epidemiological study for Asian dialysis patients has been performed. We analyzed the database of the Japanese Society for Dialysis Therapy registry. In this study, data from patients who were on HD at the end of 2000 was compiled. The Cox's proportional hazard analysis was carried out to evaluate the significance of the impact of variables related to bone mineral metabolism on survival after adjusting for possible confounding variables. The study period was three years, and a cohort of 27 404 HD patients was studied. The hazard ratios were 1.098 (P = 0.0129) for serum calcium levels ranging 10.0-10.9 mg/dL, and 1.243 (P = 0.0001) for serum calcium levels >11.0 mg/dL when the reference serum calcium level range was 9.0-9.9 mg/dL. Similarly, the hazard ratios were significantly higher in a serum phosphorous level of 5.0 mg/dL than for the reference serum phosphorous level range of 4.0-4.9 mg/dL. For intact parathyroid hormone (iPTH), the hazard ratios were significantly small (<119 pg/mL) when the reference iPTH level range was 180-359 pg/mL. However, the hazard ratio did not increase when the iPTH level increased to >360 pg/mL. Results showed that disturbances in bone mineral metabolism, such as those involving serum calcium, phosphorous, and iPTH, have a significant impact on survival in Japanese dialysis patients.

[Clinical practice guidelines for severe renal hyperparathyroidism].

Clinical practice guidelines for bone metabolism and disease in chronic kidney disease (CKD) proposed parathyroidectomy (PTX) in patients with CKD. As surgical indications, the guideline recommended that PTX should be performed in patients with severe hyperparathyroidism (persistent serum i-PTH > 800 pg/mL), associated with hypercalcemia and/or hyperphosphatemia that are refractory to medical treatment. However, the indications are not well defined and there are no studies to define absolute biomedical criteria. The clinical studies is needed to define appropriate indications for surgical treatment. It was confirmed that effective surgical therapy of severe secondary hyperparathyroidism can be accomplished by subtotal PTX or total PTX with autograft.

[Parathyroidectomy for advanced renal hyperparathyroidim in hemodialysis].

Treatment of advanced secondary hyperparathyroidism should be shifted from to avoid progression of bone disease to protection of cardiovascular complications induced by ectopic calcification. Patients who suffer from advanced secondary hyperparathyroidism with uncontrollable hypercalcemia or/and hyperphosphatemia by medical treatment should be referred to surgical treatment at relatively early time. Total parathyroidectomy with forearm autograft is adequate operative procedure especially in patients who require long-term hemodialysis.

Changes of bone remodeling immediately after parathyroidectomy for secondary hyperparathyroidism.

BACKGROUND: Successful parathyroidectomy for secondary hyperparathyroidism alleviates bone pain and is followed by the development of hypophosphatemia and hypocalcemia, as well as an increase in bone mineral density. An increase in osteoblast surface (Ob.S/BS) is not observed several months after surgery. In this study, we investigated early bone changes at 1 week after parathyroidectomy and the mechanism underlying an increase in bone mineral density. METHODS: Fourteen patients with severe secondary hyperparathyroidism underwent iliac bone biopsy before and 1 week after parathyroidectomy. Changes in histomorphometric parameters, including osteoclast surface (Oc.S/BS), eroded surface (ES/BS), erosion depth (E.De), fibrosis volume (Fb.V/TV), Ob.S/BS, osteoid volume (OV/BV), osteoid surface (OS/BS), and osteoid thickness (O.Th), were investigated. Changes in texture of mineralized bone and osteoid seams were also investigated. RESULTS: Oc.S/BS (P < 0.001), ES/BS (P < 0.01), and E.De (P < 0.001) decreased, but Fb.V/TV did not change at 1 week postoperatively. In particular, osteoclasts disappeared in almost all patients. Ob.S/BS (P < 0.001) increased, and cuboidal osteoblasts were proliferating on the trabecular surface where osteoclasts had existed before parathyroidectomy. As a result, newly developed osteoblasts coexisted with fibrous tissue after surgery. OV/BV (P < 0.005), OS/BS (P < 0.005), and O.Th (P < 0.005) increased, with lamellar osteoid volume showing a particular increase. Bone mineralization continued despite the low postoperative serum parathyroid hormone level. CONCLUSION: A rapid decrease in serum parathyroid hormone level after parathyroidectomy appears to suppress bone resorption, as well as cause a transient marked increase in bone formation and an increase in normal lamellar osteoid seams.