“Ideal” parathyroid hormone in erythropoietin‐stimulating agents‐resistant anemia

Abstract Erythropoietin‐stimulating agents (ESAs) have revolutionized anemia treatment in end‐stage renal disease (ESRD), but ESA resistance is increasingly identified. Secondary hyperparathyroidism (SHP) is one cause of ESA resistance. We describe a patient with ESA‐resistant, transfusion‐dependent anemia and mild SHP with remodeling and reticulin fibrosis on bone marrow biopsy, all of which resolved with stricter SHP management. We identified 64 patients with anemia, ESRD, and bone marrow biopsy. The parathyroid hormone (PTH) range for bony remodeling was 183–16,161.9 pg/ml versus 90.8–3283 pg/ml. The PTH range for fibrotic changes was 183–2487 pg/ml versus 90.8–16,161.9 pg/ml. We found no clear PTH range predictive for bone marrow changes.

anemia has not been determined and likely vary from subject to subject.
In this paper, we describe a patient with ESRD, SHP and associated bone marrow changes in the setting of transfusion-dependent anemia. With treatment of SHP, the bone marrow findings and transfusion dependence is completely reversed. In addition, we share descriptive findings of bone marrow biopsies in patients with anemia and ESRD in our center.

CASE PRESENTATION
A 68-year-old male with a history of ESRD secondary to type 2 diabetes and hypertension was referred to our hematology clinic for  Figure 1A).
Our clinical evaluation revealed a normal SPEP, kappa/lambda free light chain ratio, and a mildly low copper at 0.57 mcg/ml (0.85-1.8).
PTH was modestly elevated at 400.5 pg/ml

RETROSPECTIVE CHART REVIEW
The study was determined to be exempt by the institutional review board at our institution. The electronic medical record was queried for 64 patients with ESRD, anemia, and bone marrow biopsy performed between December 2010 and October 2020 and reviewed at our institution. Charts were individually reviewed for demographic factors, dialysis history (e.g., adherence, modality), and bone marrow biopsy morphological findings.
The results of our chart review are presented in Table 1  The relationship between SHP and anemia has long been described in the realm of parathyroidectomy. Zingraff et al. [5] first described the phenomenon of increased mean hematocrit following parathyroidectomy in a small series of patients with ESRD. One potential hypothesis suggests that elevated PTH contributes to a shorter erythrocyte life span. Wu et al. [6] demonstrated that ESRD patients with higher levels of PTH had increased osmotic fragility, thus decreasing erythrocyte life span and worsening anemia. What appears to be more relevant in the setting of our patient is the changes associated with SHP at the level of the bone and marrow. One potential mechanism for this relationship, seen in our patient, is increased bone turnover in more severe SHP. Rao et al. [7] showed that anemic ESRD patients who had a poor response to EPO agents had higher levels of PTH and had higher percentages of osteoclastic, eroded bone surfaces. A second suggested mechanism for anemia in SHP is fibrosis, which was also manifested in our patient as reticulin fibrosis. Brickmann et al. [8] demonstrated that elevated PTH levels in patients with ESRD appear to induce fibrosis in the bone marrow. The above study by Rao et al. further showed that ESRD patients with poor EPO response had increased degrees of bone marrow fibrosis [7].
Irrespective of the mechanism by which SHP contributes to ESAresistant anemia, it appears that intervention improves anemia, as was seen in our patient. Historically, Barbour et al. [9] described a phenomenon in which patients with ESRD and SHP had increased hematocrit following parathyroidectomy. In the following decades, subsequent studies have demonstrated that medical management of SHP may improve anemia in ESRD. In SHP, both calcitriol and cinacalcet have been shown to increase hematocrit and decrease ESA dose [10][11][12], similar to our patient who became transfusion independent following cinacalcet administration.
While the literature does seem to indicate that there is a strong relationship between SHP and ESA-resistant anemia, treatment of SHP is primarily dictated by goals in PTH, vitamin D, calcium, and phosphorus levels; even these goals that dictate clinical practice are not always scientifically based [10]. No guidelines currently exist on PTH goals in the treatment of SHP when targeting improvement in ESA-resistant anemia. As described earlier with our patient and our single-center data, there appears to be great variability in the relationship between PTH level and both anemia and bone marrow changes. One ideal PTH level for the entire dialysis-dependent population is not appropriate nor feasible. The above study using cinacalcet by Mpio et al. [11] tar- infections. Based on the findings with our patient and our institutional cohort, we suggest that it is justified to deviate from "on-size-fits-all" protocols and attempt a trial of aggressive management of SHP in patients with difficult to manage ESA-resistant anemia and more modest PTH elevation.

AUTHOR CONTRIBUTIONS
Taha Bat, Olga K. Weinberg, Orson W. Moe and Ibrahim Ibrahim designed the study and reviewed and edited the paper. Bilal Ashraf performed the research and wrote the paper. All authors analyzed the data and approved the submission.