Journal of Surgery

Introduction

Secondary Hyperparathyroidism (sHPT) is a hallmark complication of End-Stage Renal Disease (ESRD) and a central component of Chronic Kidney Disease-Mineral And Bone Disorder (CKD-MBD) [1]. The condition is driven by a complex interplay of phosphate retention, reduced synthesis of active vitamin D (calcitriol), and subsequent hypocalcemia, which collectively stimulate the parathyroid glands to overproduce Parathyroid Hormone (PTH) in an attempt to normalize serum calcium. Secondary HPT is potentially reversible when the chronic kidney disease is addressed by kidney transplantation. However, prolonged sHPT leads to severe clinical consequences, including renal osteodystrophy [2], an increased risk of bone fractures, intractable pruritus, and accelerated vascular and valvular calcification, which independently drives cardiovascular morbidity and mortality in the dialysis population [3-5]. Furthermore, the presence of secondary hyperparathyroidism has been shown to decrease kidney graft survival and increase all-cause mortality following renal transplantation [6-8], whereas performing parathyroidectomy (PTx) prior to transplantation is protective and decreases the risk of future graft failure [9]. The management of sHPT primarily relies on pharmacological therapies. The standard armamentarium includes dietary phosphate restriction combined with phosphate binders, active vitamin D analogues to suppress PTH synthesis, and calcimimetics, which competes with calcium at the calciumsensing receptor on the parathyroid gland, resulting in reduced PTH secretion [10]. While these medical therapies are effective for many patients, a significant subset develops progressive sHPT, characterized by autonomous nodular hyperplasia of the parathyroid glands that no longer responds to pharmacological suppression. For patients with medically refractory sHPT, clinical guidelines— including those from Kidney Disease: Improving Global Outcomes (KDIGO) [11], the KDOQI US Commentary [12], and the German S2k guidelines on operative therapy of renal hyperparathyroidism [13]—recommend surgical PTx. PTx has been shown to rapidly correct biochemical abnormalities, significantly reduce the risk of fractures [14], and confer a substantial survival benefit compared to continued medical therapy in refractory cases [15-17]. However, anecdotal evidence and registry data suggest that PTx rates have declined globally since the introduction of calcimimetics [18, 19], raising concerns about the potential underutilization of surgery. The real-world decision-making process leading to referral or non-referral for PTx remains poorly understood. In particular, the relative contribution of physician-, patient-, and system-level factors has not been systematically evaluated. This study aimed to evaluate the real-world prevalence of sHPT, the patterns and efficacy of medical therapy, and the clinical decision-making process regarding PTx in a contemporary multicenter cohort of dialysis patients.

Material and Methods

Study Design and Population

We conducted a multicenter retrospective cohort study of 177 dialysis patients between 2019 and 2020 treated at two tertiary centers: the University Hospital Zurich (USZ, n=60) and the Ente Ospedaliero Cantonale (EOC, n=117) (Figure 1). The cohort included adult patients undergoing maintenance dialysis for ESRD. This study was approved by the ethical boards of the Canton Zurich and the Canton Ticino.

Data Collection and Variables

Data were extracted from electronic medical records and compiled into a standardized database. The primary variables of interest included:

• sHPT Diagnosis: The presence or absence of clinically diagnosed sHPT, defined as PTH above normal range.
• Medical Therapy: The prescription of specific pharmacological agents for sHPT, categorized into vitamin D analogues, phosphate binders, and calcimimetics.
• Treatment Outcome: The clinical failure of medical therapy, defined according to the KDIGO guidelines 2006 if PTH > 800 pg/mL (> 9x upper boundary range), hyperphosphatemia and/or hypercalcemia are present twice over a time period of more than 6 months, or if there is an increase in symptoms of secondary hyperparathyroidism such as bone pain, bone fractures, or calciphylaxis.
• Surgical Decision-Making: For patients identified as having medical treatment failure, we analyzed whether PTx was performed. If PTx was not performed, the clinical rationale was assessed from the treating nephrologist (e.g., patient refusal, surgical unfitness, physician judgment of non-indication).

Statistical Analysis

Descriptive statistics were used to summarize the cohort characteristics. Categorical variables were expressed as frequencies and percentages. The analysis focused on the cascade of care, from initial diagnosis through medical treatment to surgical referral. Differences between the two study centers were also evaluated.

Figure 1: Patient Cascade: Secondary Hyperparathyroidism Management.

Results

Patient Characteristics

A total of 177 patients were included in the study, of whom 60 were enrolled at the University Hospital Zurich (USZ) and 117 at the Ente Ospedaliero Cantonale (EOC). The median age of the cohort was 77.2 years (IQR 68.6–82.4), with a female predominance (69.5%). The majority of patients were on haemodialysis (92.7%), with a median dialysis duration of 63.0 months (IQR 34.0–83.5). A history of prior kidney transplantation was documented in 54 patients (30.5%), and late referral to nephrology care was recorded in 15 patients (12.6% of those with available data). Full patient characteristics are presented in Table 1. Several clinically relevant differences between the two centers were identified.

Table 1: Patient Characteristics.

The prevalence of diabetes mellitus was higher at EOC (53.0%) than at USZ (33.3%), as was the prevalence of arterial hypertension (92.3% vs. 76.7%), COPD (29.1% vs. 8.3%), and stroke (16.2% vs. 6.7%). Accordingly, the median Charlson Comorbidity Index was higher at EOC (8.0 [IQR 7.0–10.0]) than at USZ (5.0 [IQR 3.8–8.0]), suggesting a greater overall comorbidity burden in the EOC cohort. Regarding the primary cause of chronic kidney disease, hypertension (25.0% vs. 14.5%) and diabetes mellitus (13.3% vs. 25.6%) were distributed differently between centers, with a higher proportion of unknown or undocumented aetiology at EOC (35.0% vs. 15.0% at USZ). Smoking status also differed markedly: current smoking was substantially more prevalent at EOC (19.4%) than at USZ (1.7%), while USZ had a higher proportion of never-smokers (72.9% vs. 51.5%). Race data were largely unavailable at USZ (80.0% missing), precluding meaningful inter-center comparison of ethnicity. Baseline laboratory values at the time of sHPT diagnosis showed comparable 25-OH vitamin D levels (USZ: 25.9 nmol/L [IQR 13.5–36.0]; EOC: 20.8 nmol/L [IQR 12.6–30.1]) and ionised calcium (USZ: 1.1 mmol/L [IQR 1.0–1.2]; EOC: 1.1 mmol/L [IQR 1.1–1.2]) between centers. Baseline iPTH levels were comparable between the two centers (USZ: 34.8 pmol/L [IQR 24.0–49.2]; EOC: 33.3 pmol/L [IQR 20.6–53.4]).

Prevalence of sHPT

Secondary hyperparathyroidism was nearly universal in this dialysis cohort. Of the 177 patients evaluated, 166 (93.8%) had a confirmed diagnosis of sHPT. Only 8 patients (4.5%) did not have sHPT, and data were missing for 3 patients (1.7%) (Figure 1).

Patterns of Medical Therapy

The majority of the cohort received pharmacological treatment for sHPT. Medical therapy was prescribed to 144 patients (81.4%), while 32 patients (18.1%) received no targeted sHPT medication (Table 1). The overall rate of medical therapy was similar between the two centers, with 76.7% (46/60) of patients at USZ and 84.5% (98/116) of patients at EOC receiving pharmacological treatment (Table 2). The utilization of specific drug classes varied significantly, though the patterns were largely consistent across both centers (Table 2):

• Vitamin D analogues were the most frequently prescribed agents, utilized by 137 patients (77.4% of the total cohort). This included 76.7% of patients at USZ and 79.1% at EOC.
• Phosphate binders were prescribed to 87 patients (49.2%). Utilization was slightly higher at USZ (53.3%) compared to EOC (47.4%).
• Calcimimetics were the least utilized class, prescribed to only 32 patients (18.1%). Prescription rates were comparable between centers (20.0% at USZ vs. 17.4% at EOC).
• Combination therapy was common, reflecting the standard stepwise approach to managing CKD-MBD.

Table 2: Medical Treatment Medication Patterns in Dialysis Patients with Shpt.

Efficacy of Medical Management

Medical therapy achieved successful control of sHPT in 111 patients, representing 62.7% of the total cohort. However, a substantial proportion of patients—62 individuals (35.0%)—experienced treatment failure, defined as refractory sHPT despite medical intervention. Outcome data were missing for 4 patients (2.3%) (Table 3).

The primary reasons for treatment failure among these 62 patients were hyperphosphatemia (46/56 with available data, 82.1%) and persistently elevated PTH > 800pg/mL (9/56, 16.1%). Clinical symptoms such as bone pain (4/56, 7.1%) and bone fractures (1/56, 1.8%) were less frequently documented as the primary cause of failure (Table 3). Treatment failure rates differed significantly between the two centers. At USZ, 70.0% (42/60) of patients experienced treatment failure, compared to only 17.1% (20/117) at EOC (Table 3).

Table 3: Therapeutic Outcomes of sHPT Management in the Total Cohort (N=177).