NDT Advance Access originally published online on November 9, 2006
Nephrology Dialysis Transplantation 2007 22(2):637-640; doi:10.1093/ndt/gfl547
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Use of cinacalcet in a patient on long-term dialysis with end-stage renal failure and refractory secondary hyperparathyroidism
KfH Kuratorium für Dialyse und Nierentransplantation e.V., Kronach, Germany
Correspondence and offprint requests to: Oliver Dorsch, Kuratorium für Dialyse und Nierentransplantation e.V., Kronach, Germany. Email: oliver.dorsch{at}kfh-dialyse.de
Keywords: calcimimetics; cinacalcet; hyperparathyroidism
 |
Introduction |
|---|
 Top Introduction CaseDiscussionAcknowledgementsReferences |
|---|
Progressive secondary hyperparathyroidism (sHPT) is a serious complication of chronic renal failure (CRF) caused by cellular transformation of parathyroid glands leading to aggressive growth potential and diminished expression of both the vitamin D receptor and calcium-sensing receptor (CaSR) [1]. These changes precipitate increased secretion of parathyroid hormone (PTH) (>400 pg/ml) and disruptions in the homeostatic control of serum calcium, serum phosphate and vitamin D [2,3].
While many patients with sHPT can be managed by conventional pharmacological therapy (oral phosphate binders, oral or intravenous calcitriol) and/or dietary restrictions or supplementation, these treatments fail to control disease progression in some patients. Pharmacological treatments for sHPT may also be associated with severe side effects [3], leading to vascular and soft tissue calcification [4]. Parathyroidectomy is a successful treatment for advanced autonomous sHPT that is unresponsive to medical treatment. However, sHPT may persist and progress if residual parathyroid gland tissue remains or if supernumerary glands are overlooked [5]. In addition, approximately 20% of patients who undergo autograft after parathyroidectomy develop graft-dependent recurrent hyperparathyroidism [6].
Regardless of cause, treatment-refractory patients with persistent sHPT are at risk of serious clinical complications including muscle weakness, osteodystrophy and soft tissue and vascular calcification [2]. Vascular calcification [7] and PTH levels >476 pg/ml [8] have been independently associated with an increased risk of a fatal cardiovascular event.
Clinical management of dialysis patients with sHPT is particularly challenging and effective treatments are needed. Cinacalcet, a new calcimimetic agent that targets the CaSR on parathyroid cells and increases its sensitivity to calcium [9], may fill this therapeutic gap. Cinacalcet has recently been approved for the treatment of sHPT in patients with chronic kidney disease on dialysis.
|
Case |
|---|
|
TopIntroductionCaseDiscussionAcknowledgementsReferences |
|---|
We report the case of a 56-year-old female with terminal CRF, who had been treated with haemodialysis (5 h duration 3 times weekly) for a period of 25 years. While there is no clear resolution as to the underlying source of renal insufficiency, we consider chronic glomerulonephritis to be the most likely cause.
In 1980, the patient received a kidney transplant, but this was excised a year later because immunological complications rendered it functionless. A year later, she was diagnosed with pulmonary and abdominal tuberculosis triggered by immunosuppression and, in 1990, was found to have a highly replicative (15 million IU/ml) form of hepatitis C (genotype 1a), for which she has so far declined treatment.
The gradual development of sHPT over several years further complicated the patient's condition and, by 1991, her symptoms were refractory to conventional pharmacological treatment. In the same year, she underwent total parathyroidectomy with right forearm autograft. The graft consisted of 30 slivers of parathyroid tissue implanted into the left brachioradialis muscle.
The first signs of coronary heart disease appeared 9 years later; additionally arterial calcification, aortic valve stenosis and severe calcification of the posterior mitral leaflet leading to reduced mobility were diagnosed. The patient underwent revascularization of the right coronary artery via percutaneous transluminal coronary angioplasty and stent. In 2004, she also underwent aortic valve replacement for high-grade aortic stenosis. She subsequently developed ischaemic colitis, indicative of severe cardiovascular morbidity.
During 2004, despite active vitamin D therapy (calcitriol) and good control of phosphate levels which, at <5.3 mg/dl, were within National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) recommended target levels, we observed a renewed gradual increase in PTH levels. At this time, serum calcium levels also increased to 2.65 mmol/l, restricting calcitriol therapy. The patient, however, refused to be referred for further diagnostic tests and treatment. She developed progressive and diffuse skeletal pain, primarily affecting the lower extremities and back, which persisted even at rest and prevented her from driving even short distances. An NMR scan in 2005 revealed three lesions in the distal right femur, which had sclerotic rims indicative of brown tumours.
In January 2005, Bio-Intact assays 1-84 (Nichols Institute Diagnostics, USA) revealed PTH levels which, at 44.37 pmol/l, were well above the NKF–K/DOQI upper target levels of 31.8 pmol/l. Further diagnostic assays using blood drawn separately from the antecubital vein of both arms revealed much higher PTH levels in the right arm, which had the parathyroid graft, compared with the left ungrafted arm (655 vs 40.8 pmol/l, respectively) indicating graft hyperfunction, and the need for operative revision. Magnetic resonance imaging performed prior to surgery allowed exact localization of the enlarged autograft tissue (Figure 1). Two months later, parathyroid gland tissue (dimensions 1.5 x 1.0 x 1.0 cm) was removed from the forearm as completely as possible and without complication. Despite apparently successful surgery [histological examination of the excised tissue showed parathyroid tissue (Figure 2)], post-operative serum calcium levels remained unchanged and above levels recommended by NKF-K/DOQI guidelines [10], while within 5 days of surgery PTH levels increased to 57.5 pmol/l from pre-operative levels of 44.37 pmol/l. Faced with the challenge of how to effectively reduce PTH levels in this patient, we decided to initiate treatment with cinacalcet.
|
|
Daily dosing of cinacalcet 30 mg started in March 2005 and was titrated up over the following 6 weeks to 60 mg/day. However, the immediate and rapid decline in PTH levels (to <10 pmol/l by mid April) allowed us to down-titrate cinacalcet to 30 mg/day (Figure 3). One month later, the sustained response to treatment enabled us to extend the dosing interval to three times weekly in May, and, 2 months later, to biweekly intervals (Figure 3). PTH levels remained at or below 10 pmol/l throughout treatment (Figure 3). During treatment, phosphate levels remained below NKF-K/DOQI recommendations with one exception (June 2005), while calcium levels decreased from 2.5 to
2.0 mmol/l (Figure 4). To boost plasma calcium levels (which had fallen below the NKF-K/DOQI recommended range of 2.10–2.37 mmol/l) and thus avoid increasing PTH secretion, treatment with calcitriol (up to 0.5 µg/day) was initiated in April 2005. Calcitriol dosage and dialysate calcium (June 2006, 1.5 mmol/l) concentrations were adjusted as appropriate to achieve the target levels of calcium and phosphate.
|
|
Since starting treatment with cinacalcet, the patient's general physical condition has improved and skeletal pain has diminished. No side effects related to cinacalcet administration have been observed.
|
Discussion |
|---|
|
TopIntroductionCaseDiscussionAcknowledgementsReferences |
|---|
Failure of patients with sHPT to achieve NKF international recommendations [10] for levels of PTH (15.9–31.8 pmol/l), calcium (2.10–2.37 mmol/l), phosphate (3.5–5.5 mg/dl) and Ca x P product (<4.44 mmol2/l2) is linked to a significantly increased risk of mortality. Reports of the use of new calcimimetic agents in patients with refractory sHPT to achieve these potentially difficult targets are beginning to emerge [11,12].
In randomized, double-blind, placebo-controlled clinical trials involving dialysis patients with end-stage renal disease and uncontrolled sHPT, cinacalcet was effective, for up to 4 years, in reducing levels of serum PTH and levels of serum phosphate and calcium–phosphate product, which are independent markers of an increased risk of cardiovascular disease and mortality [13–15]. Analysis of pooled data from the four similarly designed trials enrolling 1184 subjects (697 cinacalcet, 487 control) with end-stage renal disease and refractory sHPT showed that treatment with cinacalcet significantly reduces the need for parathyroidectomy, the risk of fracture and hospitalization due to cardiovascular events compared with placebo [3].
Fluck and colleagues [11] have recently described the treatment of 30 patients (29 dialysis, 1 kidney transplant; 72% with tertiary HPT) with cinacalcet. Despite the short study period (median of 2.5 months) and low dose (median dose 30 mg/day), median serum PTH decreased from 1468 to 802 pg/l (P < 0.0001) (median reduction of 43%). Median serum calcium and phosphate levels also decreased from 2.36 to 2.25 mmol/l (P = 0.04) and from 1.66 to 1.53 mmol/l (P = 0.01), respectively. A significant number of patients reported clinical improvements of HPT-related symptoms, such as bone pain. Cinacalcet has also been shown to be effective in the control of HPT in an elderly patient with malignant transformation of autotransplanted parathyroid tissue [12].
Our patient's recurrent HPT had developed over a period of more than 10 years; reduction of PTH to within levels recommended by international guidelines [10] was not achievable using conventional pharmacological treatments or ‘rescue’ surgery. Our patient suffered graft-dependent recurrent HPT following forearm autograft of parathyroid tissue, which was not resolved by surgical removal of affected tissue probably due to its infiltrative growth into musculature and indistinct boundaries. The need to effectively control PTH levels in this patient was critical due to renal osteodystrophy, skeletal pain and cardiovascular status. In contrast with conventional therapy, treatment with cinacalcet provided a rapid decrease in PTH levels, despite the presence of autonomous parathyroid tissue. The sustained response obtained allowed us to decrease dosage almost immediately. In addition, through concurrent dietetic strategies, we were able to achieve NKF-K/DOQI target levels for calcium and phosphate. In parallel with corrective changes in blood parameters, the patient's diffuse skeletal pain was reversed and physical strength restored, indicating that these symptoms had been caused by sHPT.
In summary, our data showing a rapid response to cinacalcet treatment further support the use of this agent in CRF patients with uncontrolled sHPT. The rapid response to treatment, reported in this and other reports [11,12], is particularly important to CRF patients who are at high risk of cardiovascular disease. The timely onset of adequate treatment with cinacalcet for therapy of refractory hyperparathyroidism may contribute, in contrast to conventional drug therapy, to the prevention of progressive damage to the skeletal apparatus or to the cardiovascular system. Cinacalcet therefore offers a new and promising therapeutic option in this group of patients.
|
Acknowledgements |
|---|
|
TopIntroductionCaseDiscussionAcknowledgementsReferences |
|---|
The author thanks StirlingWord Ltd, UK for the writing support and Amgen GmbH, Munich, Germany for funding it.
Conflict of interest statement. None declared.
|
References |
|---|
|
TopIntroductionCaseDiscussionAcknowledgementsReferences |
|---|
- Tominaga Y. (2000) Management of renal hyperparathyroidism. Biomed Pharmacother 54:Suppl 1, 25–31.[Medline]
- Hoerl WH. (2004) The clinical consequences of secondary hyperparathyroidism: focus on clinical outcomes. Nephrol Dial Transplant 19:Suppl 5, V2–V8.
- Cunningham J, Danese M, Olson K, Klassen P, Chertow GM. (2005) Effects of the calcimimetic cinacalcet on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Kidney Int 68:1793–1800.[CrossRef][Web of Science][Medline]
- Drüeke TB. (2004) Calcimimetics versus vitamin D: what are their relative roles? Blood Purif 22:38–43.[CrossRef][Web of Science][Medline]
- Tominaga Y, Katayama A, Sato T, et al. (2003) Re-operation is frequently required when parathyroid glands remain after initial parathyroidectomy for advanced secondary hyperparathyroidism in uraemic patients. Nephrol Hypertens 18:Suppl 3, 65–70.
- Tominaga Y, Numano M, Tanaka Y, Uchida K, Takagi H. (1997) Surgical treatment of renal hyperparathyroidism. Semin Surg Oncol 13:87–97.[CrossRef][Web of Science][Medline]
- Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. (2001) Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:939–942.
- Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK. (2001) Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 12:2131–2138.
[Abstract/Free Full Text] - Quarles LD, Sherrard DJ, Adler S, et al. (2003) The calcimimetic AMG 073 as a potential treatment for secondaryhyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 14:575–583.
[Abstract/Free Full Text] - National Kidney Foundation. (2003) K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Kidney Disease Outcomes Quality Initiative. Am J Kidney Dis 42:Suppl 3, S1–S201.[Medline]
- Fluck R, Taal M, MacIntyre C, Symes F. ( July 2006) Cinacalcet in severe hyperparathyroidism. Poster presented at XLIII ERA-EDTA Congress. , Glasgow, UK15–18 (SP343).
- Dattolo P, Michelassi S, Ferro G, et al. ( July 2006) Cinacalcet is effective in the treatment of hyperparathyroidism secondary to malignant transformation of autotransplanted parathyroid tissue. Poster presented at XLIII ERA-EDTA Congress. , Glasgow, UK15–18 (SP344).
- Moe SM, Goodman WG, Cunningham J, et al. ( June 2005) Cinacalcet sustains long-term control of secondary hyperparathyroidism (HPT). Poster presented at 36th Annual Meeting of the American Society for Neurochemistry(Madison, Wisconsin, USA) pp. 25–29 (F-P0755).
- Block GA, Martin KJ, de Francisco AL, et al. (2004) Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Eng J Med 350:1516–1525.
[Abstract/Free Full Text] - Moe SM, Cunningham J, Bommer J, et al. (2005) Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet. Nephrol Dial Transplant 20:2186–2193.
[Abstract/Free Full Text]
Accepted in revised form: 14. 8.06
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||