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Targets for parathyroid hormone in secondary hyperparathyroidism: is a “one-size-fits-all” approach appropriate? A prospective incident cohort study

  • Emmanuelle Laurain1,
  • Carole Ayav2,
  • Marie-Line Erpelding2,
  • Michèle Kessler1,
  • Serge Briançon2,
  • Laurent Brunaud3 and
  • Luc Frimat1, 2Email author
Contributed equally
BMC Nephrology201415:132

DOI: 10.1186/1471-2369-15-132

Received: 3 December 2013

Accepted: 2 July 2014

Published: 13 August 2014

Abstract

Background

Recommendations for secondary hyperparathyroidism (SHPT) consider that a “one-size-fits-all” target enables efficacy of care. In routine clinical practice, SHPT continues to pose diagnosis and treatment challenges. One hypothesis that could explain these difficulties is that dialysis population with SHPT is not homogeneous.

Methods

EPHEYL is a prospective, multicenter, pharmacoepidemiological study including chronic dialysis patients (≥3 months) with newly SHPT diagnosis, i.e. parathyroid hormone (PTH) ≥500 ng/L for the first time, or initiation of cinacalcet, or parathyroidectomy. Multiple correspondence analysis and ascendant hierarchical clustering on clinico-biological (symptoms, PTH, plasma phosphorus and alkaline phosphatase) and treatment of SHPT (cinacalcet, vitamin D, calcium, or calcium-free calcic phosphate binder) were performed to identify distinct phenotypes.

Results

305 patients (261 with incident PTH ≥ 500 ng/L; 44 with cinacalcet initiation) were included. Their mean age was 67 ± 15 years, and 60% were men, 92% on hemodialysis and 8% on peritoneal dialysis. Four subgroups of SHPT patients were identified: 1/ “intermediate” phenotype with hyperphosphatemia without hypocalcemia (n = 113); 2/ younger patients with severe comorbidities, hyperphosphatemia and hypocalcemia, despite SHPT multiple medical treatments, suggesting poor adherence (n = 73); 3/ elderly patients with few cardiovascular comorbidities, controlled phospho-calcium balance, higher PTH, and few treatments (n = 75); 4/ patients who initiated cinacalcet (n = 43). The quality criterion of the model had a cut-off of 14 (>2), suggesting a relevant classification.

Conclusion

In real life, dialysis patients with newly diagnosed SHPT constitute a very heterogeneous population. A “one-size-fits-all” target approach is probably not appropriate. Therapeutic management needs to be adjusted to the 4 different phenotypes.

Keywords

Dialysis Secondary hyperparathyroidism Cinacalcet Pharmacoepidemiological study

Background

In the 70’s, secondary hyperparathyroidism (SHPT) was described as a severe bone disease occurring in young end-stage renal disease (ESRD) patients with significant duration of dialysis. When parathyroid hormone (PTH) was very high, up to 1000 ng/L, associated with hypercalcemia, the only treatment was subtotal parathyroïdectomy [1, 2]. In the 90’s, access to kidney transplantation for the young and dialysis for the old led to a rapid ageing of dialyzed population [3]. During the first decade of the millennium, a new paradigm emerged. First, SHPT was considered not only as a bone disease, but also as a vascular disease [4]. Second, SHPT turned out to be a biological rather than a clinical disease at bedside [5]. A “one-size-fits-all” approach was recommended: PTH under 300ng/L from 2003 to 2009 according to K-DOQI [6]. Due to variability in PTH measurement, the target was modified in 2009: “maintaining PTH levels in the range of approximately two to nine times the upper normal limit for the assay” [7, 8]. Third, cinacalcet tends to be seen by the clinicians as the most appropriate solution for the treatment of SHPT due to its mechanism of action, when conventional therapy is not effective enough [6, 9]. But the randomized controlled EVOLVE study, published in 2012, failed to demonstrate efficacy of cinacalcet to reduce the risk of death or major cardiovascular events [10]. Today, the exact importance of PTH is still debated [11].

Large observational cross-sectional studies about SHPT have recently been published [1215]. An incidence/prevalence bias may have hampered a precise description of SHPT phenotypes [16]. In order to capture the phenotypes of SHPT at bedside, we meticulously enrolled all dialysis patients of the REIN registry - Region of Lorraine with newly marked PTH elevation in a prospective observational study from December 2009 to May 2012. At inclusion, we delivered a validated questionnaire to measure clinical symptoms. With an original statistical analysis, we demonstrated that high PTH levels matched with 4 very different phenotype profiles, suggesting that a “one-size-fits-all” target approach for SHPT was not appropriate.

Methods

The pharmacoepidemiological EPHEYL (Étude PHarmacoÉpidémiologique de l’hYperparathyroïdie secondaire en Lorraine) study is a 2-year, open-cohort, prospective, observational study on incident SHPT, i.e. newly diagnosed, with a 2-year follow-up, set in the 12 dialysis units located in the French region of Lorraine (public or private).

Inclusion criteria

Adult patients included in EPHEYL were on dialysis (hemodialysis or peritoneal dialysis) for at least 3 months with one of the following criteria: for the first time 1) PTH ≥ 500ng/L, 2) initiation of cinacalcet, 3) parathyroidectomy if severe SHPT. The PTH cut-off value of 500 ng/L was chosen at the time of 2003 K-DOQI [6]. Indeed, when we initiated the study, the updated KDIGO recommendations were not effective, and PTH levels between 150 and 300 ng/L were advocated [6, 8]. The indication for parathyroidectomy or the use of a calcimimetic were retained when PTH level was ≥ 500 ng/L, hence the choice of this threshold in our study.

From 1st December, 2009 to 31st May, 2012, all patients who were on dialysis for at least 3 months were identified through the REIN registry - Region of Lorraine [17]. The occurrence of one out of the three inclusion criteria was prospectively followed up in all these patients.

Patients were included in the study at the time of PTH dosing, initiation of cinacalcet, or parathyroidectomy.

Physicians were encouraged to adhere to the KDIGO™ guidelines updated in 2009 [8].

Data collection

The following socio-demographic and clinical data were retrieved from the REIN registry: age, gender, body mass index (BMI), type of dialysis, dialysis vintage, primary etiology of nephropathy, comorbidities (smoking, diabetes, cardiovascular diseases, hypertension, respiratory diseases and cancer), and being on renal transplant waiting list [17]. The vast majority of patients were Caucasians.

BMI was described as a continuous quantitative variable and obesity (BMI >30 kg/m2) as a binary variable. Primary etiology of nephropathy was classified into diabetic nephropathy, vascular nephropathy, glomerulonephritis, pyelonephritis, hereditary nephropathy, and other/unknown. Cardiovascular diseases comprised history of heart failure, cardiac heart disease, acute coronary syndrome, arrhythmia, peripheral arterial disease, and stroke. Respiratory diseases encompassed history of chronic respiratory insufficiency, asthma, and obstructive pulmonary disease. Hypertension was considered present if: diastolic and/or systolic blood pressure greater than 80 and 130 mm Hg, respectively, or a current antihypertensive therapy.

SHPT symptoms experienced by patients were assessed by using: 1) the Parathyroidectomy Assessment of Symptoms (PAS) questionnaire. This self-administered questionnaire validated in dialysis patients with SHPT assessed the severity of 14 SHPT symptoms (Table 1) experienced by patients using a visual analog scale (VAS) which ranged from 0 (not experiencing any symptom) to 100 (experiencing the most extreme aspect of the symptom) [1820]. This questionnaire was administered at the time of inclusion. PAS scores were analyzed as quantitative variables or proportion of patients with at least one symptom scoring more than 0; 2) the collection of clinical signs reported in medical records such as osteoarticular pain, myasthenia, bone fractures, paresthesia, pruritus, tetany, and calciphylaxis. A patient was symptomatic if at least one symptom had a PAS score greater than 0 or was reported in his medical records.
Table 1

Specific symptoms assessed by the parathyroidectomy assessment of symptoms (PAS) questionnaire, a self-administered disease-specific outcome tool, in patients with secondary hyperparathyroidism (SHPT)

 

Items in PAS questionnaire

1.

Pain in the bones

2.

Feeling tired easily

3.

Mood swings

4.

Feeling “blue” or depressed

5.

Pain in the abdomen

6.

Feeling weak

7.

Feeling irritable

8.

Pain in the joints

9.

Forgetfulness

10.

Difficulty to stand up

11.

Headaches

12.

Dry skin

13.

Being thirsty

14.

Pruritus

The following biological parameters were collected at the time of inclusion: PTH, calcemia, phosphorus, vitamin D, alkaline phosphatase (ALP), albumin, hemoglobin and measured ionized calcium. KDIGO™ guidelines have recommended to maintain PTH up to 2 to 9-fold above the normal range [8]. PTH was therefore described as binary variable (in or out of target) and quantitative variable (multiple of upper normal limit). According to KDIGO™ guidelines, calcemia was checked as hypo-, normo- or hypercalcemia using 2.1 and 2.6 mmol/L as cut-off values; phosphatemia as hypo-, normo- et hyperphosphatemia using 0.8 and 1,45 mmol/L as cut-off values. ALP was analyzed according to 2 stages using medians as cut-off values, albuminuria according to 2 stages using 25 g/L as cut-off value, and hemoglobin according to 3 stages using 10 and 12 g/dL as cut-off values.

Four technologies were used for PTH dosing: chemiluminometric technology (48%), electro cheminulometric method (23%), immuno-enzymology (11%), immune chemiluminometric technology (16%), and unknown (2%); each kit was provided by several laboratories which had different standards.

All drugs acting on phospho-calcic metabolism were collected and classified into 4 groups: vitamin D and analogs, calcium supplementation, calcium-free phosphorus binders, and cinacalcet.

A standardized form was used to collect data from medical records. A Steering Committee consisting of an epidemiologist (CLA) and a nephrologist (LF) reviewed all forms and medical records when collected biological data were out of international standards.

Ethics statement

This study was conducted in compliance with French regulations concerning pharmaco-epidemiological studies [21]. Approvals from the French data protection agency (CNIL: n° 904163) and from the Advisory Committee on information processing research in the field of health located in the region of Lorraine (CCTIRS: n° 0428) were obtained through the national REIN registry. An information sheet was displayed in all dialysis units, and each patient was given an individual written information sheet at the initiation of dialysis.

Statistical analyses

Patient characteristics were described as proportions for categorical variables, and means and standard deviations (SD) for continuous variables, except PAS scores described as medians.

Multivariate analyses using multiple correspondence analysis (MCA) and ascendant hierarchical clustering on clinical, biological and therapeutic characteristics of SHPT were performed to identify subgroups of patients [22]. All these parameters were binary variables.

MCA was applied to determine the major axes summarizing more clearly data [22]. This method gives a set of coordinates of the categories of variables, and thus reveals the relationships between the individuals and the different categories. Each principal component was interpreted in terms of amount of contribution for each category to variance of axis. The contribution of a variable was statistically significant when its mean was greater than 1/p, (p = number of categories of variables). Graphical evaluation was built using the major components in a series of two-dimensional graphs.

Then an ascendant hierarchical clustering was used to determine the number of subgroups on the basis of coordinates of the main components retained by MCA. The 4 clustered subgroups were numbered according to the order of the selection for the classification. The validity of this method was measured by the “cubic clustering criterion” with a cut-off of 2. After subgroups were selected, χ2 tests were performed to compare and highlight parameters defining each distinct profile of patients.

The statistical analyses were performed using SAS software, version 9.2 (SAS Institute, North Carolina, US).

Results

Patients

A total of 2137 patients who were on dialysis for at least 3 months, with PTH < 500 ng/L were retrieved from the REIN registry – Region of Lorraine between 1st December, 2009 and 31st May, 2012. Among them, 305 patients were included in the EPHEYL study: 86% with an incident PTH ≥500 ng/L (n = 261), 14% with an initiation of cinacalcet (n = 44), and 0% with a first-line parathyroidectomy (Figure 1).
https://static-content.springer.com/image/art%3A10.1186%2F1471-2369-15-132/MediaObjects/12882_2013_Article_916_Fig1_HTML.jpg
Figure 1

Disposition of patients. aParathyroid hormone.

There was no statistically significant difference in socio-demographic and clinical characteristics between both groups according to inclusion criteria (Table 2). Regarding PTH levels, 10 different values for the upper normal limit were obtained, and ranged from 38.8 to 638 ng/L (median value: 560 ng/L). Despite these high values PTH remained in the KDIGO™ target range in 64% of patients.The distribution of PTH according to multiples of the upper normal limit revealed that 60% of patients maintained PTH up to 8-fold above the upper normal limit (Figure 2).
Table 2

Socio-demographic, clinical and biological characteristics for the EPHEYL population according to inclusion criteria

  

Inclusion criteria

 
 

Study population

Cinacalcet

PTHa ≥ 500 ng/L

 
 

(N = 305)

(N = 44, 14.4%)

(N = 261, 85.6%)

 

Variables

N

 

N

 

N

 

p

Ageb, years

305

66.6 ± 15.3

44

63.3 ± 14.2

261

67.1 ± 15.4

0.122

Gender (males), %

305

60

44

71

261

58

0.126

BMIc,b, kg/m2

301

28.6 ± 6.9

44

28.3 ± 6.3

257

28.7 ± 7.1

0.697

 >30 kg/m2, %

301

33.8

44

29.5

257

34.5

0.522

Type of dialysis, %

304

 

44

 

261

 

0.340

 Hemodialysis

 

91.8

 

95.5

 

91.2

 

 Peritoneal dialysis

 

8.2

 

4.5

 

8.8

 

Dialysis vintageb, months

305

27.5 ± 34.5

44

23.1 ± 24.5

261

28.3 ± 35.9

0.362

On transplant waiting list, %

300

 

44

 

256

 

0.636

 Yes

 

8.3

 

11.4

 

7.9

 

 No

 

91.7

 

88.6

 

92.1

 

Primary etiology of nephropathy, %

300

 

43

 

257

 

0.211

 Diabetic nephropathy

 

16.0

 

23.3

 

14.8

 

 Vascular nephropathy

 

16.3

 

20.9

 

15.6

 

 Glomerulonephritis

 

10

 

11.6

 

9.7

 

 Pyelonephritis

 

4.7

 

7.0

 

4.3

 

 Hereditary nephropathy

 

7.7

 

11.6

 

7.0

 

 Others/Unknown

 

45.3

 

36.2

 

48.7

 

Comorbidities, %

305

 

44

 

261

  

 Cardiovascular diseases

 

49.5

 

45.5

 

50.2

0.561

 Diabetes

 

44.9

 

31.8

 

47.1

0.590

 Respiratory diseases

 

11.5

 

15.9

 

10.7

0.319

 Cancer

 

13.1

 

6.8

 

14.2

0.181

 Hypertension

 

85.9

 

88.6

 

85.4

0.573

 Smoking

 

13.4

 

13.6

 

13.4

0.675

Clinical signs, %

305

 

44

 

261

  

 Reported in medical records

 

27.2

 

31.8

 

26.4

0.458

 Reporded in PASd questionnaire

 

44.9

 

31.8

 

47.1

0.059

  Pain in the bones e

125

17

12

6

110

21

0.317

  Feeling tired easily e

131

47

13

50

115

46

0.054

  Mood swings e

124

23

13

20

108

23

0.216

  Feeling “blue” or depressed e

123

6

12

6

108

6

0.184

  Pain in the abdomen e

124

12

11

4

110

13

0.055

  Feeling weak e

126

48

12

23

111

49

0.067

  Feeling irritable e

123

20

12

21

108

20

0.081

  Pain in the joints e

128

40

13

52

112

39

0.130

  Forgetfulness e

126

12

14

12

109

12

0.317

  Difficulty to stand up e

121

18

10

6

108

20

0.020

  Headache e

115

5

11

13

101

5

0.372

  Dry skin e

122

35

13

49

106

30

0.325

  Being thirsty e

121

51

13

51

105

51

0.265

  Pruritus e

122

20

12

49

107

16

0.302

 Symptomatic patients, %

122

58

12

52.3

107

59

0.402

Biological parameters

       

 PTHa,b, ng/L

305

619 ± 226

44

468 ± 262

261

644 ± 210

<0.0001

  within KDIGO target f , %

305

64.3

44

81.8

261

61.3

0.009

 Serum calciumb, mg/L

305

87.0 ± 7.1

44

81.8 ± 7.1

261

87.1 ± 7.2

0.681

 Calcemia, %

305

 

44

   

0.935

  ≤ 84 mg/L

 

42.6

 

43.2

 

42.5

 

  84-104 mg/L

 

57.4

 

56.8

 

57.5

 

  > 104 mg/L

 

0

 

0

261

0

 

 Serum phosphorusb, mg/L

305

54.4 ± 16.5

44

50.9 ± 17.6

261

55.0 ± 16.3

0.129

 Phosphatemia, %

305

 

44

   

0.675

  <25 mg/L

 

2.6

 

2.3

 

2.7

 

  25-45 mg/L

 

28.6

 

34.1

 

27.6

 

  >45 mg/L

 

68.9

 

63.6

 

69.7

 

 Serum alkaline phosphataseb, UI/L

299

103.4 ± 56.9

43

124.3 ± 97.0

256

99.9 ± 46.3

0.009

 Bicarbonatemiab, mmol/L

303

22.2 ± 3.4

44

22.4 ± 2.8

258

22.1 ± 3.5

0.618

 Albuminb, g/L

291

36.3 ± 4.6

42

36.7 ± 4.1

249

36.2 ± 4.6

0.504

 Hemoglobinb, g/dL

279

10.3 ± 1.6

44

10.6 ± 1.5

235

10.3 ± 1.6

0.245

 Vitamin Db, ng/mL

209

19.2 ± 13.5

31

15.8 ± 10.4

178

19.7 ± 13.9

0.138

 Ionised calciumb, mmol/L

58

1.1 ± 0.2

3

0.9 ± 0.8

55

1.1 ± 0.1

0.031

Treatment, %

305

 

44

 

261

  

 Vitamin D (per os)

 

63.9

 

72.7

 

62.5

0.189

 Calcium

 

68.9

 

81.8

 

66.7

0.045

 Phosphorus binders

 

59.3

 

61.4

 

59 0

0.768

 Cinacalcet at inclusion

 

14.4

 

100

 

0

<0.0001

 Cinacalcet at 3 months

 

27.2

 

56.8

 

22.2

<0.0001

aParathyroid hormone; bResults are presented as mean ± SD; cBody mass index; dParathyroidectomy Assessment of Symptoms; eMedian value; fThe 2009 updated KDIGOTM (Kidney Disease: Improving Global Outcomes) guidelines have recommended target range for serum PTH to 2–9 times upper the normal range [8].

https://static-content.springer.com/image/art%3A10.1186%2F1471-2369-15-132/MediaObjects/12882_2013_Article_916_Fig2_HTML.jpg
Figure 2

Distribution of parathyroid hormone (PTH) according to multiples of the upper normal limit for the assays in the EPHEYL study.

Among the 44 patients treated with cinacalcet, 36 patients had PTH within the KDIGO™ target range before initiating the treatment. At 3 months of inclusion, 19 patients (43%) discontinued treatment with cinacalcet.

Cluster analysis

Ascendant hierarchical clustering identified four subgroups of patients according to their SHPT profiles as shown Figure 3. The “cubic clustering criterion” of the model was 14, higher than the cut-off of 2, validating the classification.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2369-15-132/MediaObjects/12882_2013_Article_916_Fig3_HTML.jpg
Figure 3

Identification of four distinct subgroups of dialysis patients with secondary hyperparathyroidism (SHPT) using multiple correspondence analyses. The horizontal axis defined the presence or absence of calcium supplementation, the presence or absence of treatment with cinacalcet, and serum PTH below or above 500 ng/L. The vertical axis defined a normophosphatemia, a hyperphosphatemia, the absence or presence of phosphorus binders, high or low level of alkaline phosphatases, the presence or absence of vitamin D supplementation, the presence or absence of calcium suplementation. Each patient is identified by a number and a color according to the following code: black for group 1 (“intermediate”), green for group 2 (younger with severe cardiovascular comorbidities), blue for group 3 (elderly patients with few cardiovascular comorbidities), pink for group 4 (“cinacalcet prescription”).

The four clustered subgroups of patients were named according to their main characteristics regarding variables used (Table 3) or not used for clustering patients (Table 4):
Table 3

Characteristics of dialysis subgroups identified at time of secondary hyperparathyroidism (SHPT) diagnosis: variables used to cluster dialysis patients at time of SHPT diagnosis

Variables

Group 1a

Group 2a

Group 3a

Group 4a

 
 

(N = 113, 37.2%)

(N = 73, 24.0%)

(N = 75, 24.7%)

(N = 43, 14.1%)

p

Clinical signs, %

     

 All clinical signs

64

55

56

54

0.512

 Clinical signs reported in PASb

55

45

37

33

0.031

Biological parameters

     

 PTHc,d, ng/L

666 ± 182

630 ± 199

635 ± 233

449 ± 255

<0.0001

  within KDIGO target, %

51

66

69

86

0.0004

 Serum calciumd, mg/L

89 ± 7

82 ± 6

89 ± 6

87 ± 7

<0.0001

  Hypocalcemia, %

29

81

27

42

<0.0001

 Serum phosphorusd, mg/L

58 ± 17

62 ± 13

44 ± 12

52 ± 17

<0.0001

  Hyperphosphatemia, %

81

96

25

67

<0.0001

  Hypophosphatemia, %

4

4

0

2

<0.0001

 Serum alkaline phosphatased, UI/L

100 ± 44

78 ± 29

120 ± 53

123 ± 99

<0.0001

  Under median value, %

50

84

21

53

<0.0001

Treatments, %

     

 Vitamin D and analogs

73

84

24

77

<0.0001

 Calcium supplementation

68

95

35

86

<0.0001

 Calcium-free phosphorus binders

58

93

25

65

<0.0001

 Cinacalcet

0

0

3

98

<0.0001

aGroup 1: “intermediate” patients, Group 2: younger patients with severe comorbidities, Group 3: elderly patients with few cardiovascular comorbidities, Group 4: patients who initiated cinacalcet; bParathyroidectomy Assessment of Symptoms questionnaire; cParathyroid hormone; dResults are presented as mean ± SD; p corresponds to ANOVA.

Table 4

Characteristics of dialysis subgroups identified at time of secondary hyperparathyroidism (SHPT) diagnosis: variables not used to cluster dialysis patients at time of SHPT diagnosis

Variables

Group 1a

Group 2a

Group 3a

Group 4a

 
 

(N = 113, 37.2%)

(N = 73, 24%)

(N = 75, 24.7%)

(N = 43, 14.1%)

p

Socio-demographic

     

 Ageb, years

65 ± 17

66 ± 14

72 ± 13

63 ± 15

0.008

 Gender (males), %

56

66

55

70

0.217

Dialysis

     

 Type of dialysis, %

    

0.330

  Hemodialysis

90

96

91

95

 

  Peritoneal dialysis

10

4

9

5

 

 Dialysis vintageb, months

27 ± 32

19 ± 22

38 ± 48

24 ± 24

0.007

Comorbidities, %

     

 Cardiovascular diseases

48

62

41

47

0.086

 Diabetes

46

55

41

30

0.070

 BMIc, kg/m2

29

30

27

28

0.217

  >30 kg/m 2 , %

37

42

23

30

0.091

Biological parameters

     

 Albuminb, g/L

37 ± 5

36 ± 5

36 ± 5

37 ± 4

0.396

 Hemoglobinb, g/dL

10.0 ± 1.6

10.4 ± 1.5

10.6 ± 1.7

10.6 ± 1.5

0.046

aGroup 1: “intermediate” patients, Group 2: younger patients with severe comorbidities, Group 3: elderly patients with few cardiovascular co-morbidities, Group 4: patients who initiated cinacalcet; bResults are presented as mean ± SD; cBody mass index; p corresponds to ANOVA.

– “Intermediate” patients (Group 1, 37%): patients with hyperphosphatemia without hypocalcemia, sharing similar characteristics with the next group of patients (Group 2) but better controlled

– Younger patients with severe cardiovascular comorbidities (Group 2, 24%): most often obese or diabetic patients, with shorter dialysis vintage, mainly with hyperphosphatemia and hypocalcemia despite multiple medical treatments, suggesting poor adherence

– Elderly patients with a few cardiovascular comorbidities (Group 3, 25%): rarely obese, with longer dialysis vintage, mainly with normophosphatemia and normocalcemia despite few patients with SHPT treatment, with health status appearing to be, at first, much better than the one in group 2

– Patients who initiated cinacalcet (Group 4, 14%): 42 out of the 44 patients who initiated cinacalcet and another patient were classified into a clearly distinct subgroup (Figure 3). Two patients treated with cinacalcet were classified into other groups.

Discussion

EPHEYL is a well-characterized cohort of patients with incident severe SHPT diagnosis described not only on the basis of initiation of cinacalcet but also a cut-off value for PTH [6]. An incident population helps to accurately describe diseases, avoiding bias related to incidence and prevalence mix [16]. We used an appropriate methodology, MCA and ascendant hierarchical clustering, to identify homogeneous subgroups of cases with a high statistical level validity [22]. Our four clustered subgroups consisted of homogeneous patients with same medical history, same prior therapy, and probably similar characteristics concerning mineral bone diseases and cardiovascular co-morbidities.

SHPT symptoms are difficult to assess due to the lack of specificity. The self-administered questionnaire developed by Pasieka et al. was used in several studies on primary and secondary hyperparathyroidism to quantify severity of symptoms using median values [1820]. In the EPHEYL study, one out of two patients suffered from at least one symptom. But the most frequent symptoms (thirst, weakness, fatigue, and pain of joints) were not specific. As the questionnaire was developed in the context of parathyroidectomy, its validity is questionable at early stage of SHPT.

The PTH cut-off value of 500 ng/L was chosen at the time of 2003 K-DOQI [6]. Its enabled to focus on SHPT patients without adynamic bone disease [8, 23]. Furthermore, no patient had hypercalcemia, suggesting that there was no tertiary or autonomized SHPT. This result is consistent with the incident type of our cohort, as tertiary SHPT were found in previous studies including prevalent SHPT patients [6, 24]. Nevertheless, we know that PTH is subject to many simultaneous types of variability [7, 11]. Our study points out obstacles with the use of PTH to precisely diagnose SHPT. The distribution of PTH at a cut-off value of 500, according to the new recommendation: “maintaining PTH levels in the range of approximately two to nine times the upper normal limit for the assay” was wide (Figure 2). Jean et al. have suggested that PTH should be replaced with specific biochemical markers of bone such as bone ALP and beta cross-laps to follow-up SHPT [24]. These measurements, however, are too costly to be recommended in routine clinical practice [8]. Finally, in the context of quite vague recommendations, clinicians should be aware that a binary approach for SHPT diagnosis, i.e. absence/presence, is not adequate. There is definitely a grey zone for diagnosis which limits are not easily defined. We should recommend an observation period before acting strongly.

In this grey zone, our study identified four statistically distinct subgroups of patients. Our description of each group reflected a clinical reality, and was therefore clinically appropriate. Noteworthy, at bedside, these distinct phenotypes should be distinguished by doctor rather by biological cut-offs. This pleads for patient-doctor contact. A recent publication has demonstrated a positive association between patient-doctor contact and outcomes [25]. Last but not least, our study reinforces the recent publication by Levin that has recommended acknowledging the heterogeneity of chronic kidney disease populations and appropriately characterizing populations for studies [26].

The group of “elderly patients with a few cardiovascular comorbidities”, in majority with normocalcemia and normophosphatemia, had a PTH which, at first, should impressed clinicians. In another hand, normal serum phosphorus could not be explained by malnutrition; despite their old age, nutritional markers (such as albumin and phosphatemia) were not statistically different from those in the other groups. PTH seemed to be associated with a good clinical condition and a low prevalence of comorbidities. These results are consistent with those from previous studies in showing that, particularly in elderly, PTH is inversely correlated with score of comorbidities [12, 27]. At the time of diagnosis of SHPT, this subgroup of patients did not require presumably an intensive therapeutic management.

The group of “younger patients with severe cardiovascular comorbidities”, by contrast, consisted of a majority of patients (66%) with PTH within targets [8]. However, the mean PTH was similar to the one found in the previous group. They seemed to be most likely to have bone and cardiovascular complications, as in previous cohorts, possibly linked to hyperphosphatemia, with a high proportion of cardiovascular diseases, diabetes and obesity [4, 13]. As a result, they should require an intensive care management. Of note, most of them had hyperphosphatemia and hypocalcemia despite multiple treatments. It is obvious that this phenotype is characterized by very low adherence to first-line strategies for SHPT, e.g. calcium, vitamin D and phosphorus binders. For this treatment category, a recent meta-analysis has pointed out poor adherence in a majority of patients [28].

The group of “intermediate patients” seemed to show intermediate characteristics between those with both previous groups. Most of them had hyperphosphatemia without hypocalcemia and the highest PTH. They seemed to be more likely to be at high risk for cardiovascular events due to uncontrolled hyperphosphatemia; as a result, they should be cautiously monitored [21].Finally, the group of patients “who initiated cinacalcet” was very different from the others (Figure 3). Most of patients had hypocalcemia and hyperphosphatemia. Patients were given already multiple conventional treatments before cinacalcet initiation. At the time of cinacalcet initiation, an overwhelming majority of patients (86%) had PTH within KDIGO™ targets which were applicable during the study period. Our study has confirmed that cinacalcet was prescribed for broadened indications in real life, and highlighted that the benefit-risk balance of cinacalcet was not favorable in patients with low PTH. This phenotype “cinacalcet user” including such patients should not exist. Before such therapeutic agents were marketed, indications for surgical parathyroidectomy were limited to symptomatic SHPT patients with very high PTH (>1000 ng/L). Initially presented as an alternative to parathyroidectomy, cinacalcet is now prescribed in pre-symptomatic patients with PTH > 300 ng/L, perhaps due to previous KDOQI recommendations.

Its prescription is based on studies suggesting that cinacalcet should have a protective effect on cardiovascular disease outcomes and reduce risk of fractures [29]. Recently, the prospective EVOLVE study failed to demonstrate the role of cinacalcet in reducing cardiovascular mortality and events [10]. These negative results can be explained, in particular, by the fact that 23% of patients in the treated group and 11% in the placebo group received the trade formulation of cinacalcet, which skewed the results. The EPHEYL study has shown that the use of cinacalcet was likely to be physician-dependent rather than characteristic of patients, and decision-making to prescribe it was insufficiently detailed. Thus in the group of patients who initiated cinacalcet, 43% of them who should have been treated with cinacalcet were not taking treatment 3 months later. Considering that low PTH levels characterize adynamic bone disease and/or a high prevalence of comorbidities, we should currently recommend to prescribe cinacalcet only after conducting a rigorous investigation on its benefit/risks [23, 27]. The strength of our study was to identify a subgroup of incident SHPT patients treated with cinacalcet despite low PTH in a real life setting. The matter whether cinacalcet should be contraindicated in patients with low PTH is of great interest.

Our study has some limitations. Its observational nature which may seem like a drawback is strength actually. Pharmacoepidemiological study, as EPHEYL, reflects routine clinical practices with various therapeutic strategies which are not always consistent with previous randomized trials [10]. Second, we have taken into account only data at the inclusion, making sense as regards to the incident nature of a disease. The 2-year follow-up of the EPHEYL cohort should reinforce the relevance of the classification. Third, most of patients were included with a PTH cut-off value of 500ng/L, while the latest KDIGO™ guidelines have recommended maintaining PTH in ranges, at approximately 2 to 9 times the upper normal limit, rather than absolute values. KDIGO™ recommendations were not implemented when we wrote our article. As a result, data on PTH have been detailed in this report. Fourth, the methodology allowed identification of distinct profiles, not completely disjunctive. It is therefore possible that some patients of distinct subgroups should have partially similar characteristics at junctions. Notwithstanding differences between groups are relevant. Fifth, clinical symptoms assessed by PAS questionnaire need to be interpreted with caution, due to the difficulty met to collect data from self-administered questionnaire.

Conclusion

In conclusion, four significantly distinct profiles of dialysis patients with a recent severe SHPT diagnosis were identified on the basis of clinical, biological and therapeutic data routinely available. Our well-characterized incident cohort, coupled with an original methodological approach, highlights a contemporary picture of daily clinical practice. Our study reinforces that the benefit-risk balance of cinacalcet is not positive in patients with low PTH, and raises the matter whether cinacalcet should be contraindicated in such patients. A “one-size-fits-all” target for PTH approach is probably not appropriate. Therapeutic management needs to be adjusted to the four different phenotypes.

Notes

Declarations

Acknowledgements

We are extremely grateful to the patients who contributed to this study. We thank all nephrologists and hospital directors who participated in the study, particularly the study nurse, Catherine Campagnac.

EPHEYL received a public funding from Clinical Research Hospital Program (“PHRC inter-regional 2009”) of the French Health Ministry and “Agence de la Biomedicine” (2008).

Authors’ Affiliations

(1)
Department of Nephrology, University Hospital, University of Lorraine
(2)
EA 4360 Apemac, Nancy University, P. Verlaine Metz University, and Paris Descartes University
(3)
Department of General, Digestive and Endocrine Surgery, University Hospital, University of Lorraine

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  30. Pre-publication history

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© Laurain et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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