Kyra Borchhardt

Cinacalcet increases calcium excretion in hypercalcemic hyperparathyroidism after kidney transplantation.

Background. Cinacalcet reduces serum calcium in kidney transplant recipients with hypercalcemic hyperparathyroidism. The mechanism of action is not fully understood. We hypothesized that cinacalcet increases renal elimination of calcium, thereby improving hypercalcemia in kidney transplant recipients. Methods. We prospectively examined the effect of cinacalcet (30 mg/d) during the first 6 weeks of treatment on serum and 24 hrs urinary calcium concentration and calculated fractional calcium excretion in 32 patients with sustained hypercalcemic hyperparathyroidism (Ca >2.6 mmol/L [10.4 mg/dL], intact parathyroid hormone >60 pg/mL). Secondary endpoints were serum phosphate and tubular maximum of phosphate corrected for glomerular filtration rate, intact parathyroid hormone and serum creatinine. Results. Serum calcium concentrations decreased in all patients (from 2.77 to 2.51 mmol/L; P<0.0001), fractional calcium excretion increased rapidly in the first 2 weeks of treatment from 1.06 to 1.78% (P<0.0001), and decreased thereafter to 1.37% (P<0.05 vs. early treatment). Simultaneously serum phosphate and tubular maximum of phosphate corrected for glomerular filtration rate increased significantly from 0.79 to 0.85 to 0.88 mmol/L (P<0.05), and from 0.52 to 0.61 (P<0.005) and 0.62 (P<0.0001 vs. baseline), respectively. Intact parathyroid hormone did not decrease significantly. Serum creatinine remained stable. Conclusion. We provide evidence that the calcium lowering effect of cinacalcet in patients with persistent hyperparathyroidism after kidney transplantation is caused, at least in part, by increased urinary calcium excretion.

Cinacalcet Decreases Bone Formation Rate in Hypercalcemic Hyperparathyroidism after Kidney Transplantation

Background/Aims: Cinacalcet reduces serum calcium in kidney transplant recipients with hypercalcemic hyperparathyroidism. Its effect on bone, however, has not been investigated in this population. Methods: We prospectively examined bone turnover, histomorphometry and density as well as serum bone biomarkers in 10 transplant recipients before and after treatment with cinacalcet. Results: After 18–24 months of treatment with cinacalcet, bone formation decreased in 7, increased in 2, and remained zero in 1 patient (p = 0.11). Trabecular bone volume was maintained. Trabecular number decreased (p = 0.03), but trabecular thickness was unchanged (p = 0.17). Osteoid decreased (p = 0.02) and osteoblast surface increased (p = 0.02). Bone mineral density of the femur remained stable in 1 patient, decreased in 2 patients, but increased in 7 patients (p = 0.153). Serum calcium concentration (p = 0.005), iPTH (p = 0.01) and calcitonin concentration decreased (p = 0.03), while 25(OH) vitamin D3 increased (p = 0.02). No fractures were reported. Graft function remained stable. Conclusion: Whilecinacalcet might decrease bone formation rate, it did not change bone volume, and bone mineral density of the femur increased. Therefore, the use of cinacalcet in hypercalcemic hyperparathyroidism might be safe with regard to the bone disease present after kidney transplantation.

Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials.

Background: Vitamin D deficiency has been associated with a number of diseases, including influenza. Whether or not this reflects a causal relationship is unknown. We therefore wanted to examine if supplementation with vitamin D would affect the incidence and severity of influenza-like disease. Methods: Questionnaires on influenza were sent to subjects participating in ongoing placebo-controlled intervention studies with vitamin D supplementation, up until the end of April 2010. Results: Five hundred and sixty-nine subjects from 10 different clinical trials were included in the study, of whom 289 were randomized to receive vitamin D (1111–6800 IU/day) and 280 to receive placebo. Influenza-like disease during the previous fall/winter was reported in 38 subjects in the vitamin D group and 42 in the placebo group (non-significant), of whom 25 and 26 subjects, respectively, fulfilled our clinical criteria for influenza. In these latter subjects, the duration of illness was significantly longer among those in the vitamin D group than among those in the placebo group (median 7 (range 2–60) days vs median 4 (range 2–18) days; p = 0.007). However, this difference was not statistically significant if all 38 (vitamin D) and 42 (placebo) subjects who reported symptoms were included. Conclusion: Our results do not support the hypothesis that high doses of vitamin D supplementation will have a pronounced effect on influenza-like disease in populations not targeted for high influenza risk.

VITA-D: cholecalciferol substitution in vitamin D deficient kidney transplant recipients: a randomized, placebo-controlled study to evaluate the post-transplant outcome.

BackgroundVitamin D does not only regulate calcium homeostasis but also plays an important role as an immune modulator. It influences the immune system through the induction of immune shifts and regulatory cells resulting in immunologic tolerance. As such, vitamin D is thought to exert beneficial effects within the transplant setting, especially in kidney transplant recipients, considering the high prevalence of vitamin D deficiency in kidney transplant recipients.Methods/DesignThe VITA-D study, a randomized, placebo-controlled, double-blind study with two parallel groups including a total of 200 kidney transplant recipients, is designed to investigate the immunomodulatory and renoprotective effects of cholecalciferol (vitamin D3) within the transplant setting. Kidney transplant recipients found to have vitamin D deficiency defined as 25-hydroxyvitamin D3 < 50 nmol per liter will be randomly assigned to receive either oral cholecalciferol therapy or placebo and will be followed for one year. Cholecalciferol will be administered at a dose of 6800 International Units daily over a time period of one year.The objective is to evaluate the influence of vitamin D3 substitution in vitamin D deficient kidney transplant recipients on the post-transplant outcome. As a primary endpoint glomerular filtration rate calculated with the MDRD formula (modification of diet in renal disease) one year after kidney transplantation will be evaluated. Incidence of acute rejection episodes, and the number and severity of infections (analyzed by means of C-reactive protein) within the first year after transplantation will be monitored as well. As a secondary endpoint the influence of vitamin D3 on bone mineral density within the first year post-transplant will be assessed. Three DXA analyses will be performed, one within the first four weeks post-transplant, one five months and one twelve months after kidney transplantation.Trial RegistrationClinicalTrials.gov NCT00752401

Renal function and glomerular permselectivity late after living related donor transplantation

Living related kidney transplantation is the preferable procedure for renal replacement therapy. The aim of the current study was to determine systemic hemodynamic and intrarenal adaptions in donors and recipients late after living related kidney transplantation. Furthermore, glomerular permselectivity was assessed in these subjects. We studied mean blood pressure (MAP), glomerular filtration rate (GFR), renal plasma flow (RPF), microalbuminuria (MIA), 24-hr urinary protein excretion, and glomerular permselectivity (fractional clearance of neutral dextrans [thetaD] as a marker for size selectivity and fractional clearance of dextran sulfate [thetaDS] to assess charge selectivity) in 22 donors and 22 recipients. MAP was normal in the donor group (102 +/- 4 mmHg), but five patients had blood pressure above 140/90 mmHg. This 18%, however, is lower than the prevalence of hypertension in the age-adjusted general population in Austria. The recipients also had normal MAP at the time of study (99 +/- 3); however, 13 needed antihypertensive therapy. GFR and RPF were lower in recipients than in donors (53 +/- 8 vs. 72 +/- 11 and 314 +/- 74 vs. 412 +/- 86 ml/min respectively). In the donor group, GFR was 137 +/- 45% of the expected age-adjusted mean value/kidney due to hyperfiltration. Proteinuria and MIA were higher in the recipients than in the donors (0.39 +/- 0.22 vs. 0.07 +/- 0.04 g/day, 137 +/- 136 vs. 26 +/- 15 mg/day). Nonetheless, five donors had an elevated MIA. A higher need for antihypertensive medication could be observed in recipients with previous rejection episodes, as well as a significantly higher urinary protein excretion and MIA (0.7 +/- 0.42 vs. 0.24 +/- 0.14 g/day, 336 +/- 380 vs. 48 +/- 32 mg/day). ThetaDS was significantly higher in the recipients, whereas thetaDS of the donors was identical to the value obtained from 18 healthy controls (0.7 +/- 0.08 vs. 0.6 +/- 0.06). OD was similar in all groups studied. In conclusion, 76 months after uninephrectomy for renal donation, mild changes in glomerular permselectivity occurred in a subset of donors without affecting renal excretory function. In recipients, proteinuria was due to a defect in glomerular charge selectivity.

Reversibility of ‘Secondary Hypercalcitoninemia’ After Kidney Transplantation

Whether the increase of calcitonin (CT) concentration in patients with chronic kidney disease (CKD) is reversible or not after kidney transplantation is not known. We examined the effect of kidney transplantation on basal and pentagastrin‐stimulated CT in CKD patients with elevated screening CT levels.

Prevalence of hypercalcitoninemia in patients on maintenance dialysis referred to kidney transplantation.

AIMS Elevated calcitonin concentrations in dialysis patients had led to thyroidectomy for a benign C-cell hyperplasia in dozens of patients in the past decade. The prevalence of hypercalcitoninemia, however, has not been examined in a large cohort of dialysis patients. METHODS We, therefore, measured calcitonin concentrations in 283 dialysis patients. We used different reference intervals: according to the threshold to perform further stimulation tests (i.e. > 10 pg/ml) and new reference intervals for the currently used assay (i.e. serum calcitonin concentration < 11.5 pg/ml in men and < 4.6 pg/ml in women). RESULTS Median calcitonin concentrations of men and women were 12 (1; 290) pg/ml vs 2 pg/ml (1; 45), respectively, (p < 0.0001). The prevalence of hypercalcitoninemia was 10% in women and 58% in men using a cut-off of 10 pg/ml. Applying the new reference intervals 31% of women and 54% of men presented with hypercalcitoninemia. All patients with basal calcitonin concentrations above 50 pg/ml were men (highest calcitonin concentration was 290 pg/ml). Two of them underwent thyroidectomy and had C-cell hyperplasia. CONCLUSION The prevalence of hypercalcitoninemia in dialysis patients amounts to 46%. It is more common in male than in female dialysis patients.

Long-term clinical practice experience with cinacalcet for treatment of hypercalcemic hyperparathyroidism after kidney transplantation.

Within this prospective, open-label, self-controlled study, we evaluated the long-term effects of the calcimimetic cinacalcet on calcium and phosphate homeostasis in 44 kidney transplant recipients (KTRs) with hypercalcemic hyperparathyroidism by comparing biochemical parameters of mineral metabolism between pre- and posttreatment periods. Results are described as mean differences (95% CIs) between pre- and posttreatment medians that summarize all repeated measurements of a parameter of interest between the date of initial hypercalcemia and cinacalcet initiation (median of 1.6 (IQR: 0.6–3.8) years) and up to four years after treatment start, respectively. Cinacalcet was initiated after 1.8 (0.8–4.7) years posttransplant and maintained for 6.2 (3.9–7.6) years. It significantly decreased total serum calcium (−0.30 (−0.34 to −0.26) mmol/L, P < 0.001) and parathyroid hormone levels (−79 (−103 to −55) pg/mL, P < 0.001). Serum levels of inorganic phosphate (Pi) and renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) increased simultaneously (Pi: 0.19 (0.15–0.23) mmol/L, P < 0.001, TmP/GFR: 0.20 (0.16–0.23) mmol/L, P < 0.001). In summary, cinacalcet effectively controlled hypercalcemic hyperparathyroidism in KTRs in the long-term and increased low Pi levels without causing hyperphosphatemia, pointing towards a novel indication for the use of cinacalcet in KTRs.

Low-dose calcium versus pentagastrin for stimulation of calcitonin in chronic hemodialysis patients: a pilot study.

CONTEXT Elevated calcitonin levels occur in up to 46% of patients with chronic hemodialysis (CHD) and frequently reflect benign C-cell hyperplasia rather than medullary thyroid carcinoma. For the differential diagnosis of hypercalcitoninemia, the pentagastrin-stimulated calcitonin test was used until its availability became restricted. OBJECTIVE This study sought to compare calcium and pentagastrin in terms of their ability to stimulate calcitonin secretion and their side effects in patients with CHD. SETTING AND DESIGN This prospective pilot study was conducted at the chronic hemodialysis unit of the Medical University of Vienna between December 2012 and September 2013. PATIENTS We studied six male patients with CHD with elevated basal calcitonin levels. INTERVENTION The stimulation test was performed first with 0.5 μg/kg pentagastrin and then with 1 mg/kg calcium after a median washout period of 7 (6-9) months. MAIN OUTCOME MEASURES We measured calcitonin, serum ionized calcium, intact PTH (iPTH), and C-terminal fibroblast growth factor 23 levels before and 2, 5, and 10 minutes after iv infusion of the stimulant and assessed the tolerability of the two substances by a questionnaire. RESULTS Both pentagastrin and calcium significantly stimulated calcitonin secretion at 2 and 5 minutes. Partial correlation analysis revealed a strong association between calcium- and pentagastrin-stimulated calcitonin levels (r=0.875, P < .0001). Only after calcium infusion serum ionized calcium levels increased from 1.09 (0.91-1.16) mmol/l to 1.4 (1.14-1.65) mmol/l at 2 minutes (P < .01) but returned to baseline levels at 5 minutes. Moreover, calcium infusion led to a significant decrease in iPTH levels from 315 (203-723) pg/ml to 182 (121-415) pg/ml at 5 minutes (P < .05) and 171 (91-346) pg/ml at 10 minutes (P < .001). In general, calcium caused fewer and less severe side effects than pentagastrin. CONCLUSIONS In patients with CHD, the response of calcitonin to calcium and pentagastrin was comparable, making calcium a potential substitute for pentagastrin in these patients.

Calcidiol deficiency in end-stage organ failure and after solid organ transplantation: status quo.

Among patients with organ failure, vitamin D deficiency is extremely common and frequently does not resolve after transplantation. This review crystallizes and summarizes existing data on the status quo of vitamin D deficiency in patients with organ failure and in solid organ transplant recipients. Interventional studies evaluating different treatment strategies, as well as current clinical practice guidelines and recommendations on the management of low vitamin D status in these patients are also discussed.