Restoration of renal anemia following therapy with etelcalcetide for refractory secondary hyperparathyroidism: a case report with mini-review
Renal Replacement Therapy volume 5, Article number: 16 (2019)
The patient was a 72-year-old woman who had been under dialysis for a long time to chronic renal failure of unknown etiology. Her dialysis vintage was 22 years. She was under treatment with cinacalcet for secondary hyperparathyroidism (2HPT). However, cinacalcet was withdrawn because she presented digestive complications. In March 2017, treatment with etelcalcetide, a novel intravenous calcimimetic, became possible. On April 10, 2017, her intact parathyroid hormone (PTH) level was 1150 pg/mL, and etelcalcetide 5 mg was administrated three times per week after dialysis. After 6 months, her intact PTH (iPTH) level was 283 pg/mL and her hemoglobin (Hb) level was 12.9 g/dL though she was not administered erythropoietin-stimulating agent (ESA). She had three detectable parathyroid glands. Conventionally, her parathyroid glands should have been removed; however, as her parathyroid hormone level decreased, this procedure was not required. In this patient, etelcalcetide improved severe 2HPT and renal anemia.
Secondary hyperparathyroidism (2HPT) is one of the most important complications of chronic renal failure. Elevated concentration of parathyroid hormone causes not only osteitis fibrosa but also various complication including cardiovascular problems. Besides, 2HPT is a cause of erythropoietin-stimulating agent (ESA)-resistant anemia . It has been already reported that therapy with vitamin D and cinacalcet improves renal anemia [2,3,4]. Etelcalcetide belongs to new class of drugs that target calcium-sensing receptors in the parathyroid glands. Etelcalcetide proved to be not inferior to cinacalcet in reducing serum PTH , and we think etelcalcetide is superior to cinacalcet concerning drug compliance as it is meant to be administered intravenously. We report the case of a patient in whom etelcalcetide exerted a strong suppressive effect on 2HPT and reversed renal anemia.
The patient was a 72-year-old woman who had undergone hemodialysis three times per week since 1995 for end-stage renal disease caused by an infectious disease. She had three hypertrophic parathyroid glands. Conventionally, this condition is an indication of parathyroidectomy. However, she did not desire to undergo parathyroidectomy. Therefore, she was treated with injectable vitamin D and oral cinacalcet. Moreover, the patient was initiated on maxacalcitol at a dose of 5 μg three times per week, yet the dose of maxacalcitol could not be increased because the patient showed hypercalcemia.
And cinacalcet had to be withdrawn due to gastrointestinal problem. Laboratory findings immediately before etelcalcetide treatment were as shown in Table 1. Her parathyroid glands were 1.4 × 1.2 × 1.1 cm (0.97cm3), 0.7 × 0.6 × 0.3 cm (0.07 cm3), and 0.8 × 0.7 × 0.3 cm (0.09 cm3) in size. In April 2017, she was started on etelcalcetide 5 mg three times per week. Two months later, the dose of etelcalcetide was increased to 10 mg three times per week. And after 3 months, the dose of maxacalcitol could be increased to 10 μg three times per week. After 6 months of treatment, her intact PTH (iPTH) level and her serum calculated calcium (CCa) level decreased from 1150 to 283 pg/mL and from 10.2 to 9.9 mg/dL, respectively (Fig. 1). Surprisingly, her Hb level was 12.9 g/dL without ESA (Fig. 2). Serum alkaline phosphatase (AlP) level increased after the start of etelcalcetide and then decreased to 205 U/L after 6 months. The percentage of transferrin saturation (TSAT) gradually declined from 42 to 29% after 3 months and to 23% after 6 months. Iron had never been administered in the previous year and was never administered during this observation period either. ESA preparation had been administered at least once a month during the previous year. Her serum Alb level was between 3.3 and 3.4 g/dL during the observation period. Her nutrition condition was stable. Neither fever nor leukocytosis was observed for 6 months, during treatment with etelcalcetide.
Basically, this patient had three detectable parathyroid glands and high serum concentrations of PTH. Conventionally, these findings are indication of parathyroidectomy. In general, Japanese dialysis patients are of old age, are under dialysis for a long period, and present various complications, including cardiovascular diseases. Therefore, their medical conditions are not favorable for parathyroidectomy. Because this patient presented ophthalmologic and cardiac pathologies, she rejected parathyroidectomy, and her serum concentration of PTH continued to increase. After 6 months on etelcalcetide therapy, her PTH markedly decreased. This result suggested etelcalcetide had a strong suppressive effect on PTH excretion. Besides, etelcalcetide also reduced the serum level of calcium. These results suggested that etelcalcetide had a stronger calcium-decreasing effect than cinacalcet . Cinacalcet and etelcalcetide are thought to have a similar mechanism of action in terms of their specific action in the parathyroid glands and suppression of PTH. The clinically different point is that etelcalcetide has a strong calcium-lowering effect compared to cinacalcet. Use of etelcalcetide can be expected to increase the use of vitamin D preparation as serum calcium-decreasing agent. It is known that 2HPT is associated with high bone turnover and leads to a decrease of bone mass and bone strength. Unfortunately, we did not measure bone metabolic markers. However, serum AlP level increased just after the etelcalcetide injection and then decreased to a level below the baseline value. Such AlP variation is very similar to that found in a previously reported research and which was associated with improved bone metabolic markers . Our treatment regimen may contribute to suppress bone turnover. We were able to increase the dose of maxacalcitol because of this calcium-decreasing effect of etelcalcetide. Indeed, marked hypercalcemia was seen with maxacalcitol 10 μg three times per week. In our patient, serum CCa was persistently about 10 mg/dL. Thus, etelcalcetide allowed us to easily use and increase the dose of vitamin D. The patient had been administered ESA by injection for renal anemia during the previous year. However, after etelcalcetide was started, she did not receive ESA therapy, and during 6 months, her Hb level was stable at 12 g/dL. The dialysis conditions were not changed during this treatment period. Even though iron supplementation was not done, her anemia improved. It is also suggested that the use of iron may improve anemia during this time as TSAT also declines. This result may suggest that a decrease of PTH improves ESA resistance. However, from the fact that the Hb value is maintained high by the ESA preparation administered prior to the start of etelcalcetide administration, it is not always possible to deny the long-term effects of the ESA preparation. In previous papers, it was reported that the control of PTH initially required a dose of erythropoietin that was decreased after parathyroidectomy , that vitamin D injection therapy corrected renal anemia , and that cinacalcet decreased ESA use . In the past, we reported that cinacalcet improved not only severe 2HPT (iPTH 895 pg/mL), but also anemia in another patient. However, that patient did not have parathyroid nodules . It is known that nodular parathyroid glands do not respond to medical therapy . Surprisingly, the present patient had a very high serum concentration of iPTH and three nodular parathyroid glands. Etelcalcetide may improve nodular parathyroid glands. Etelcalcetide is one of the strongest suppressive therapies for 2HPT. The frequency of parathyroidectomy for 2HPT was markedly decreased by use of cinacalcet . We think that in the future, the rate of parathyroidectomy will decrease even further by use of etelcalcetide. We have described a case of severe 2HPT that was successfully treated using etelcalcetide. This drug was not only effective for controlling 2HPT but also to restore renal anemia. As etelcalcetide is an injectable preparation, it has good compliance.
Improvement of renal anemia by PTH control
Parathyroidectomy (PTX) was the most reliable treatment for 2HPT before the use of vitamin D injection therapy. After PTX, the serum level of PTH markedly decreases, and it is reported that, as a result, endogenous erythropoietin increases and the dose of erythropoietin can be reduced [1, 7, 10,11,12]. It is known that severe 2HPT causes bone marrow fibrosis. It is thought that induction of erythropoietin is decreased by bone marrow fibrosis. Indeed, the percentages of osteoclast surface area, bone marrow fibrosis area, and eroded surface area were found to be higher in hemodialysis patients who showed a poor response to erythropoietin. Besides, those patients had higher level of PTH . Consequently, it is thought that repair of bone marrow fibrosis via a decrease of PTH by PTX restores erythropoiesis in the bone marrow.
Vitamin D therapy (Table 2)
Vitamin D therapy was the only medical treatment for 2HPT before the advent of calcimimetics. Control of PTH by vitamin D contributes to improve renal anemia. It was reported that the decrease of PTH by alfacalcidol had resulted in an increase of Hb blood concentration . Other vitamin D preparations, for example, intravenous calcitriol and paricalcitol, also normalize Hb concentration leading to a reduction of the required ESA dose [2, 15, 16]. Amelioration of osteitis fibrosa via the decrease of PTH with vitamin D medication may start to happen after around 3 months of treatment. However, these findings are supported by only a small number of studies. Vitamin D is also thought to directly improve renal anemia. It is reported that low levels of 25(OH) D are associated with lower hemoglobin concentrations . And each of these associations was found to be independent of multiple potential factors—gender, renin-angiotensin inhibitors, and inflammatory factors in no dialysis patients with chronic kidney disease . There are also studies indicating a correlation between vitamin D deficiency and anemia and have suggested that a 25-OHD level of < 30 ng/mL is a risk factor for anemia . These results imply that vitamin D contributes to ameliorate anemia in two ways, namely, through repair of osteitis fibrosa by decreasing the level of PTH and by direct stimulation of the proliferation of erythrocytes in the bone marrow.
Calcimimetics (Table 3)
Calcimimetics is the most recent treatment for 2HPT. Currently in Japan, we can use three kinds of calcimimetics. Cinacalcet is the first calcimimetic that became available in Japan. The characteristics of cinacalcet are that in addition to a strong PTH lowering effect, it also decreases the levels of calcium and phosphate . Amelioration of renal anemia by cinacalcet was reported in the form of an increase in Hb concentration and a decrease of the required dose of ESA [21, 22]. However, these two observational studies involved a small number of patients. The effect of cinacalcet in patients with renal anemia is thought to be due only to its PTH-lowering effect at present. Fusaro et al. noted that the dose of ESA could be decreased in patients treated with cinacalcet, but not in those treated with paricalcitol. This study has the following two problems. The level of PTH was suppressed much strongly in the cinacalcet group than in the paricalcitol group, and they evaluated only a very small number of patients. Although there was no significant difference between the two groups, it should be noted that in the paricalcitol group, the Hb concentration increased by 0.5 g/dL. This result cannot deny the Hb rising effect of paricalcitol . Tanaka et al. performed a study in which they used data from Japanese hemodialysis patients with 2HPT. They selected patients with a Hb level of more than 10 g/dL. There were 1337 cinacalcet users and 1864 non-users. The results of this study showed that cinacalcet could be expected to improve renal anemia. Important doubts remained in this study regarding the effect of cinacalcet on renal anemia as vitamin D was administered to many patients. They reported that 1162 (86.9%) patients in the cinacalcet group had taken vitamin D formulations . It is also undeniable that the reduction of PTH by cinacalcet may enhance the action of vitamin D on bone. Vitamin D has also been used in many patients in other studies. Etelcalcetide and evocalcet have never been reported to date for the improvement of renal anemia, but an effect similar to that of cinacalcet can be expected. Etelcalcetide has a stronger calcium-lowering effect than cinacalcet . As a result, the dose of a vitamin D preparation can also be increased, so that besides its powerful PTH lowering effect, a renal anemia-improving effect can be expected.
Conclusions of this mini review
Improvement of 2HPT by various treatments (parathyroidectomy, vitamin D therapy, and cinacalcet therapy) is thought to improve renal anemia via erythropoietin synthesis and increase of erythroid progenitor cells by direct effect of decrease of PTH synthesis and an improvement of osteitis fibrosa. Apart from that, it is also suggested that vitamin D may improve renal anemia (Fig. 3). These findings are based on only a few studies involving limited number of patients; therefore, large-scale prospective studies will be necessary in the near future to confirm these findings.
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Oshiro, Y., Nitta, T. & Oomoto, M. Restoration of renal anemia following therapy with etelcalcetide for refractory secondary hyperparathyroidism: a case report with mini-review. Ren Replace Ther 5, 16 (2019). https://doi.org/10.1186/s41100-019-0213-z