End-Stage Renal Disease Related Hyperparathyroidism
van der Plas, Willemijn
DOI:
10.33612/diss.151471102
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Publication date: 2021
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van der Plas, W. (2021). End-Stage Renal Disease Related Hyperparathyroidism: Towards a Patient-Tailored Journey. University of Groningen. https://doi.org/10.33612/diss.151471102
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Partly published as: Advances in Diagnosis and Management of Secondary Hyperparathyroidism
W.Y. van der Plas1
L. Vogt2
S. Kruijff1
1 Department of Surgery, University Medical Center Groningen, Groningen University, Groningen,
the Netherlands
2 Department of Nephrology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam,
the Netherlands
In: Advances in Treatment and Management in Surgical Endocrinology (pp. 85–99) Elsevier (2020).
General introduction
End-stage renal disease
Globally, 850 million people are affected by chronic kidney disease (CKD).1 CKD is
characterized by progressive loss of kidney function, and may ultimately lead to end-stage renal disease (ESRD), the final stage of chronic gradual loss of kidney function requiring dialysis or kidney transplantation.2 In the Netherlands, the prevalence of patients requiring
renal replacement therapy (RRT) has increased with 137% in the past decade (Figure 1).3 In 2018, the number of Dutch people receiving RRT was 17.657, and is expected to
further increase.3,4 Frequent complications of ESRD include hypertension, malnutrition,
anaemia, hyperkalaemia, increased infection risk and finally, hyperparathyroidism.5
Patients with ESRD, and particularly patients on dialysis, have a strongly increased risk of mortality, morbidity and a decreased quality of life.6,7 Cardiovascular complications,
primarily due to severe vascular calcification, are the leading cause of death in CKD patients.8–10 The pathophysiological mechanism causing vascular calcification is complex,
and not fully understood, yet disturbances in the calcium-phosphate metabolism and hyperparathyroidism are thought to play a prominent role.9
Figure 1 – Prevalence of patient on renal replacement therapy per million people (PMP)
Parathyroid glands and PTH
Parathyroid hormone (PTH) is produced by four small parathyroid glands, surrounding the thyroid gland in the neck. The parathyroid glands were first identified by Sir Richard Owen (1804 – 1892), who had been allowed to dissect and preserve all animals that died in the London Zoo.11 In 1849, after 15 years of life in captivity, an Indian rhinoceros
named Clara died during an altercation with an elephant. Sir Richard Owen spent over 12 months dissecting the 2000 kilograms weighing animal investigating the cause of
Dialysis Transplantation from deceased donor
Year PM P 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 0 250 500 750
1
her tragic death.12 Clara appeared to have broken multiple ribs causing a pneumothorax.
In his extensive anatomy report, sir Richard Owen described “a small compact yellow glandular body attached to the thyroid”.11 Subsequently, it was the Swedish medical
student Ivor Sandström (1852 – 1889) who named the glands, after identifying the glandulae parathyroideae - first in a canine specimen, and later in numerous other animal species, including 50 human bodies.13
Production and excretion of PTH by the parathyroid glands is influenced by extracellular concentration of electrolytes calcium and phosphate. The parathyroid gland is able to sense extracellular levels of calcium via the calcium-sensing receptor (CaSR) on the parathyroid cells. CaSR senses and maintains extracellular calcium concentration within a certain range by regulating parathyroid chief cell secretion of PTH.14,15 The
actions of increased extracellular levels of calcium on the CaSR lead to a reduction of serum calcium levels, mainly by inhibiting the release of secretary granules with PTH by the parathyroid glands, and increasing urinary calcium excretion.16 Apart from the
reduction of PTH secretion, CaSR stimulation reduces PTH synthesis in general, as well as parathyroid cell proliferation.17 Thus, there is a direct relationship between serum PTH
levels and levels of calcium illustrated by the sensitivity of the control mechanism.18,19 A
schematic overview of PTH physiology is depicted in Figure 2. In the bones, PTH binds to the parathyroid hormone 1 receptor (PTH1R) on osteoblasts which, via a complex ligand dependent pathway, stimulate osteoclasts. In turn, osteoclasts enhance bone resorption through which calcium is released into the bloodstream.20,21 PTH stimulates renal active
reabsorption of calcium in the distal tubule, but has the opposite effect to phosphate: it inhibits the absorption of phosphate in the proximal tubule. Lastly, PTH enhances the conversion of 25-hydroxycholecalciferol to 1,25(OH)2D, the active metabolite of vitamin D.
Calcium absorption is regulated by 1,25(OH)2D in the intestinal tract. Thus, the net effect of PTH is lowering of serum phosphate levels, while increasing the serum calcium level. In response to increased levels of 1,25(OH)2D, osteocytes and osteoclasts secrete the protein fibroblast growth factor (FGF)-23. FGF-23 acts on the sodium-phosphate cotransporter in the proximal tubules of the kidneys in the presence of membrane-bound protein Klotho, causing a decrease in the reabsorption and increase in excretion of phosphate. The net effect of FGF-23 is phosphaturia.22–24 Hyperparathyroidism (HPT) is characterized
by an increased blood concentration of parathyroid hormone (PTH). In primary HPT, this overproduction is in most cases caused by a single hyperplastic adenoma.25 In contrast,
by an external stimulus and leads to hyperplasia of all four glands. The most common cause of secondary HPT is end-stage renal disease (ESRD). Other causes include calcium malabsorption (e.g. by vitamin D deficiency, bariatric surgery or celiac disease), the use of loop diuretics, bisphosphonates, or denosumab.26 This thesis focuses on ESRD-related
secondary and tertiary HPT.
Figure 2 – Parathyroid-bone-kidney-intestine feedback loop27
Hyperparathyroidism related to end-stage renal disease
HPT secondary to renal failure has been described in case reports dating from the late 1930s and 1940s. At that time however, the prognosis of ESRD was poor and patients did not live long enough to develop severe HPT. It was only after the Dutch physician Willem Johan Kolff built the first artificial dialyzer in 1943, that the life-expectancy of patients with renal failure started to increase.28 Long-term hemodialysis was established with the
development of the arteriovenous shunt in the early 1960s by doctor Belding Scribner.29,30
Despite adequate dialysis treatment, patients with long-term ESRD develop virtually inevitably hyperphosphatemia due to impaired renal phosphate excretion, probably in part due to decreased functional renal mass, and in part due to the loss of 1,25(OH)2D.31,32
To enhance phosphate excretion, FGF-23 levels already increase in early stages of CKD.33
Secondary to a decreased serum concentration of calcium, and increased levels of serum phosphate and FGF-23, the parathyroid glands are stimulated to excrete PTH, in an
Parathyroid gland Thyroid gland PTH Bone Kidney Small intestine 1,25(OH)2D Duodenal lumen Blood
1
attempt to return to maintain balance.32 An increase in serum PTH levels can already be
observed in pre-terminal stages of kidney failure. Eventually, over 80% of patients with an estimated glomerular filtration rate (eGFR) below 20 ml/min have PTH levels above the upper limit of normal (>65 pg/mL or 6.9 pmol/L).34 In ESRD, the parathyroid glands
are chronically exposed to low extracellular calcium and high extracellular phosphate levels, first leading to polyclonal, followed by monoclonal hyperplastic parathyroid tissue.35 These morphologic changes are accompanied by a decreased expression of
both the CaSR and the vitamin D receptor (VDR), although the number of secretory chief cells as well as the total number of parathyroid cells increase.36,37 Ultimately, this
process leads to autonomous PTH synthesis and secretion, regardless of serum calcium concentrations. Hence, the parathyroid-bone-kidney feedback loop becomes irreversibly distorted. This phenomenon leads to severe hypercalcemia, also known as tertiary HPT.
The exact definitions of and distinction between secondary and tertiary HPT have been a matter of debate for many years. In general, secondary HPT is characterized by increased PTH levels in combination with hypocalcemia and hyperphosphatemia in the presence of ESRD. In tertiary HPT, patients have both increased PTH levels, as well as hypercalcemia and hyperphosphatemia, due to a disturbed feedback system after a prolonged period of secondary HPT. Tertiary HPT becomes most clear after successful kidney transplantation (KTx). By eliminating metabolic and biochemical disturbances with a successful KTx, the external stimulus triggering the parathyroid glands to produce and secrete PTH, is removed. However, HPT only resolves spontaneously in 6 out of 10 patients after KTx, thus 40% of patients have persistently elevated PTH, calcium and phosphate levels after KTx.38 The term ESRD-related HPT covers both HPT before and after KTx.
Clinical manifestations
Patients with disturbances in mineral metabolism present with various serious conditions such as: pruritus, bone pain, calciphylaxis, pathologic fractures, and muscle weakness. Many patients with increased PTH and calcium levels also present with a wide range of non-specific complaints that are less known such as concentration difficulties, feeling depressed, and forgetfulness. In the majority of patients, these symptoms in ESRD-related HPT patients result in a significant decrease in quality of life.39 Serious clinical
manifestations related to mineral and bone disorder and HPT may vary from progressive bone loss due to increased bone turnover to an increased risk of cardiovascular disease and mortality due to accelerated cardiovascular calcification.40–43 The impact of
long-term increased PTH, calcium, and phosphate levels on the kidney and especially on a future kidney transplant are a matter of debate. HPT in ESRD patients seems to be an
independent risk factor for renal graft loss and glomerular filtration rate (GFR) decline after transplantation.44,45 Lastly, ESRD-related HPT has been associated with increased
all-cause mortality.43,44
Therapeutic options
The Chronic Kidney Disease – Mineral Bone Disease (CKD-MBD) guideline by the Kidney Disease Improving Global Outcomes (KDIGO) Working Group are the only international, yet mono-disciplinary, guidelines on the treatment of ESRD-related HPT.46
Treatment options include vitamin D supplements, phosphate binders, calcimimetics, and parathyroid surgery. The management of ESRD-related HPT remains complex and correction of all mineral bone markers, including calcium, phosphate, PTH, and FGF-23 should be striven for.
Nutritional vitamin D deficiency is already seen in almost 90% of pre-dialysis patients, despite (excessive) sun exposure.47 The cause of the high prevalence of vitamin D
deficiency in the CKD population is thought to be multifactorial, including proteinuria, nutritional factors, and hyperpigmentation.48 Therefore, vitamin D repletion is one of
the first steps in the prevention of ESRD-related HPT. As phosphate retention is one of the earliest manifestations of renal excretion failure and ESRD-related HPT, phosphate binders can be initiated as soon as PTH and FGF-23 levels start to rise. Unfortunately, in almost all dialysis patients, vitamin D supplements and phosphate binders are insufficient in restoring calcium-phosphate homeostasis. Moreover, excessive supplementation of active vitamin D in a 1,25(OH)2D deficient patient may induce hypercalcemia.
Therefore, as part of PTH- and calcium-lowering therapy, calcimimetics can be added to the combination of vitamin D analogues and phosphate binders. Calcimimetics are allosteric modulators of the CaSR, not only activating the CaSR itself, but also increasing the sensitivity of the CaSR to extracellular calcium. As a result, PTH production and excretion by the parathyroid glands is inhibited.49 Calcimimetics are available both for oral
use (cinacalcet) and since 2016, for intravenous administration (etelcalcetide). To date, the majority of secondary HPT patients is managed medically. A meta-analysis comparing 24 RCTs with over 10,000 dialysis patients concluded that cinacalcet leads to a significant reduction of PTH, calcium, and phosphate.50 In 2012, the EVOLVE trial was conducted to
evaluate the impact of cinacalcet on the risk of death and nonfatal cardiovascular events in hemodialysis patients.51 In primary analyses of this large randomized controlled trial,
the authors did not find a significant difference in the risk of death or cardiovascular event between patients who used cinacalcet compared to patients receiving placebo.
1
However, in censored analysis, adjusting for age, statistical significance was reached for the primary composite endpoint. Cinacalcet is only registered for hemodialysis patients and it is not FDA approved for kidney transplant patients with persistent HPT, although frequently off-label prescribed.
This thesis mainly focuses on a more definite treatment option for ESRD-related HPT: parathyroidectomy (PTx). The first parathyroidectomy (PTx) was performed by dr. Mandl in 1925 in Vienna, in a male tram car conductor with advanced osteitis fibrosa.52 Surgeons
started to operate on the parathyroid glands in patients with ESRD-related HPT in the early 1960s. Before the calcimimetic era, PTx was the only next step when the HPT was insufficiently controlled by vitamin D analogues and/or phosphate binders. The outcomes of the preferred surgical strategies, subtotal PTx or total PTx with autotransplantation, have similar outcomes with regard to amelioration of biochemical values and risk of persistent or recurrent disease.53 The risk of mortality and cardiovascular events, and
fracture risk decreases significantly after PTx, although these observations come from retrospective uncontrolled studies.54–58
As chronic kidney failure is the underlying cause of secondary and tertiary HPT, the ultimate treatment for these patients is a kidney transplantation (KTx). Indeed, a reduction of parathyroid functional mass has been seen after kidney transplantation.38
As stated, ESRD-related HPT resolves in 57% of cases two years after KTx.
Although the biochemical impact of the available treatment options is well investigated, most options lack evidence with regard to important patient outcomes such as quality of life, overall survival, progression of renal failure, and survival of kidney transplant. There are also only a handful of studies comparing the available treatment options, or combinations of them. Therefore, most of the recommendations made by the CKD-MBD KDIGO Working Group are based on level 2 (weak) and grade B or C (moderate of low quality) evidence.46
Over time, the patient with chronic kidney disease moves through advancing stages of kidney disease, towards dialysis treatment or kidney transplantation with, in parallel, different stages of HPT. An analogy could be made with a complex underground railway system: while a patient travels from one stage of the disease to the other, it is possible to transfer to several different treatment options (Figure 3). Commonly, a patient with ESRD will receive dialysis at first, while HPT is progressing (green, blue and pink line). HPT during dialysis might be treated with calcimimetics or PTx prior before undergoing
KTx (green line). When HPT persists after kidney transplantation, a patient may receive calcimimetics (pink line). For some patients, calcimimetics will not sufficiently suppress the HPT or are not tolerated, and the patient still has to undergo PTx (blue line). In countries with a good availability of living kidney donors as the Netherlands, considerable numbers of patients receive a pre-emptive kidney transplant, averting the need for dialysis treatment (red and yellow line). Such patients have a lower risk of developing severe HPT compared to dialysis patients, but might still need either calcimimetics (yellow line) or PTx (red line). Unfortunately, sometimes a train back to a previous station needs to be taken, for example when a kidney graft fails and the patient requires dialysis treatment again (grey dashed line). Figure 3 emphasizes the complexity, variety, and versatility of patients require treatment of HPT related to ESRD. Along all these different paths a patient with ESRD travels, HPT in some degree is likely to occur and progress, which complicates finding the optimal treatment for each individual.
Figure 3 – Complex pathways of the ESRD patient with HPT
CKD
Dialysis KTx
Calcimimetics PTx
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Aim and outline of the thesis
The overall aim of this thesis is to provide evidence-based recommendations for the treatment of patients with ESRD-related HPT. Our goal is to evaluate outcomes of PTx in patients with ESRD-related HPT and to address the role of PTx and calcimimetics as potential treatment modalities in ESRD-related HPT.
Part I: ESRD-related HPT
To this purpose, the first part of this thesis reviews ESRD-related HPT and its consequences. Chapter 2 presents an overview of the pathogenesis, clinical presentation and implications, required diagnostic work-up of ESRD-related HPT and discusses indications, strategies and outcomes for the available treatment options. In Chapter 3, we assessed the relationship of serum calcium and phosphate levels with kidney graft and patient outcomes in a large cohort of kidney transplant recipients. Using 138,496 time-updated serum calcium and phosphate measurements of 2,769 kidney transplant patients, we were able to investigate the impact of increased and decreased plasma calcium and phosphate levels on kidney graft failure and all-cause mortality. By studying this relationship, better insight in therapeutic target levels for serum calcium and phosphate after transplantation is gained.
Part II: Surgical treatment for ESRD-related HPT
The second part of this thesis focuses on the outcomes of PTx in terms of safety, efficacy, and quality of life in patients with ESRD-related HPT. ESRD is a severe systemic disease which puts the patient in increased risk of complications after surgery. On top of this, as the calcium-phosphate homeostasis is a highly delicate equilibrium, abrupt changes after PTx might possibly harm the patient. Therefore, in Chapter 4, we evaluated the safety of PTx in patients with ESRD-related HPT, as well as the impact of PTx on biochemical values including PTH, calcium and phosphate. The ESRD-related HPT population is a complex and mixed patient group, because some of the patients are on dialysis, and others have received a well-functioning kidney graft. A dilemma arises when a patient might undergo KTx in the future: should PTx precede KTx to potentially improve graft outcomes, or should possible spontaneous resolution of the disease after transplantation be awaited? In Chapter 5 we assessed the impact of the timing of PTx, prior or after KTx, on renal function after KTx in 185 patients with ESRD-related HPT. Both Chapter 4 and 5 were conducted using a nationwide database collected at the initiative of the Dutch Hyperparathyroidism Study Group (DHSG).
When treating HPT, improved laboratory measurements as serum calcium and PTH levels should be achieved, but more importantly, increase in QoL should be gained. Collaborating with the University of Sao Paulo, we analysed the impact of several PTx approaches on the QoL of 69 patients on dialysis, in a randomized controlled trial comparing subtotal PTx and total PTx with autotransplantation of two different amounts of parathyroid tissue (Chapter 6). After evaluation of the current surgical practice, we assessed PTx in an era with increasing number of available kidney transplants. In this changing treatment landscape, the surgical approach for patients with ESRD-related HPT might have to change subsequently. Thus, we investigated the outcomes of selected patients that underwent a less aggressive PTx compared to the conventional subtotal or total PTx. We investigated persistent and recurrent disease rates in a prospectively collected database of 195 patients undergoing PTx for ESRD-related HPT (Chapter 7). Part III: Evaluation of the role of parathyroidectomy and calcimimetics in a changing treatment algorithm of ESRD-related HPT
Relatively new to the treatment algorithm of secondary HPT are calcimimetic agents. When the oral calcimimetic cinacalcet was introduced in 2004, calcimimetics immediately gained an important role in the treatment algorithm of ESRD-related HPT. In part three of this thesis, we compare calcimimetics with surgical treatment and evaluate how this change influenced the position of PTx in the treatment algorithm of ESRD-related HPT. After its introduction, promising results were published showing that cinacalcet lowers PTH and serum calcium levels. However, cinacalcet use is commonly accompanied by several side effects including nausea, vomiting and diarrhea.51 We therefore systematically
reviewed the literature to compare the impact of both cinacalcet and PTx on QoL of patients with ESRD-related HPT (Chapter 8). We also compared cinacalcet and PTx with regard to their impact on graft and overall survival using the national database set up by the DHSG (Chapter 9). Up to now, no randomized controlled trial has been conducted that directly compared the outcomes of dialysis patients with ESRD-related HPT undergoing PTx or using cinacalcet. Using propensity score matching, selection bias between the PTx and cinacalcet group could be reduced, and therefore they could be compared more reliably.
Next, we investigated the impact of the introduction of calcimimetics on the timing of PTx in patients with ESRD-related HPT (Chapter 10). We compare patient characteristics, time from diagnosis to surgery, and PTx efficacy and safety before and after the introduction of calcimimetics. Interestingly, after the publication of the EVOLVE trial, concluding that there is no clear evidence that cinacalcet reduces the risk of death or major cardiovascular events, cinacalcet ceased to be subsidized through the Australian
1
Pharmaceutical Benefits Scheme in 2015.51 We were therefore able to perform parallel
analyses in a Australian ESRD-related HPT population adding a third comparison group: patients who were treated after the removal of cinacalcet from the reimbursed drug list
(Chapter 11).We addressed our findings and concerns, and make our recommendations
on the treatment of ESRD-related HPT in Chapter 12 from a Dutch surgical perspective endorsed by both the International as the American Association of Endocrine Surgeons. Finally, Chapter 13 summarizes the findings of this thesis, discusses its implications, and provides an overview of the future perspectives and directions for future studies on the search for the optimal patient-tailored treatment for patients with ESRD-related HPT.
References
1. Jager KJ, Kovesdy C, Langham R, Rosenberg M, Jha V, Zoccali C. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Kidney Int 2019;96(5):1048–50.
2. Hill NR, Fatoba ST, Oke JL, et al. Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis. PLoS One 2016;11(7):e0158765.
3. Hoekstra T, Dekker F, Cransberg, Bos W, Hemmelder M. RENINE Annual Report 2018 [Internet]. 4. McCullough KP, Morgenstern H, Saran R, Herman WH, Robinson BM. Projecting ESRD incidence and
prevalence in the United States through 2030. J Am Soc Nephrol 2019;30(1):127–35.
5. Thomas R, Kanso A, Sedor JR. Chronic Kidney Disease and Its Complications. Prim. Care - Clin. Off. Pract. 2008;35(2):329–44.
6. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351(13).
7. Evans RW, Manninen DL, Garrison LP, et al. The Quality of Life of Patients with End-Stage Renal Disease. N Engl J Med 1985;312(9):553–9.
8. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am. J. Kidney Dis. 1998;32(5 SUPPL. 3).
9. Mizobuchi M, Towler D, Slatopolsky E. Vascular calcification: The killer of patients with chronic kidney disease. J. Am. Soc. Nephrol. 2009;20(7):1453–64.
10. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: Epidemiology, mechanisms, and prevention. Lancet. 2013;382(9889):339–52.
11. Owen S. On the Anatomy of the Indian Rhinoceros. Trans Zool Soc London 1862;4(2):31–58. 12. Modarai B, Sawyer A, Ellis H. The glands of Owen. J R Soc Med 2004;97(10):494–5.
13. Sandström I. Om en ny körtel hos menniskan och åtskilliga däggdjur. Ups Läk Förh 1880;XV:441–71. 14. Bräuner-Osborne H, Wellendorph P, Jensen AA. Structure, pharmacology and therapeutic prospects
of family C G-protein coupled receptors. Curr Drug Targets 2007;8(1):169–84.
15. Filopanti M, Corbetta S, Barbieri AM, Spada A. Pharmacology of the calcium sensing receptor. Clin Cases Miner Bone Metab 2013;10(3):162–5.
16. Tfelt-Hansen J, Brown EM. The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 2005;42(1):35–70.
17. Brown EM. Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab 2007;3(2):122–33.
18. Ward DT, Riccardi D. New concepts in calcium-sensing receptor pharmacology and signalling. Br J Pharmacol 2012;165(1):35–48.
19. Mayer GP, Hurst JG. Sigmoidal relationship between parathyroid hormone secretion rate and plasma calcium concentration in calves. Endocrinology 1978;102(4):1036–42.
20. Hall JE, Guyton AC. Guyton and Hall: Textbook of Medical Physiology. Philidelphia, PA: Saunders/ Elsevier; 2011.
1
2005;5(6):612–7.
22. Quarles LD. Role of FGF23 in vitamin D and phosphate metabolism: Implications in chronic kidney disease. Exp Cell Res 2012;318(9):1040–8.
23. Jüppner H. Phosphate and FGF-23. Kidney Int Suppl 2011;79(121):S24-7.
24. Razzaque MS. The FGF23–Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol 2009;5(11):611–9.
25. Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg 2016;151(10):959.
26. Rosen CJ, Bouillon R, Compston J, Rosen V. Primer on the metabolic bone diseases and disorders of mineral metabolism. 8th ed. New York: Wiley-Blackwell; 2013.
27. Created with BioRender.com.
28. Kolff W. First Clinical Experience with the Artificial Kidney. Ann Intern Med 1965;62(3):608. 29. Scribner BH, Buri R, Caner JE, Hegstrom R, Burnell JM. The treatment of chronic uremia by means of
intermittent hemodialysis: a preliminary report. Trans Am Soc Artif Intern Organs 1960;6:114–22. 30. Quinton W, Dillard D, Scribner BH. Cannulation of blood vessels for prolonged hemodialysis. Trans
Am Soc Artif Intern Organs 1960;6:104–13.
31. Hruska KA, Mathew S, Lund R, Qiu P, Pratt R. Hyperphosphatemia of chronic kidney disease. Kidney Int 2008;74(2):148–57.
32. Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol 2011;6(4):913–21.
33. Simic P, Kim W, Zhou W, et al. Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney. J Clin Invest 2020;130(3):1513–26.
34. Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: Results of the study to evaluate early kidney disease. Kidney Int 2007;71(1):31–8.
35. Drüeke TB. Cell Biology of Parathyroid Gland Hyperplasia in Chronic Renal Failure. J Am Soc Nephrol 2000;(11):1141–52.
36. Lewin E, Garfia B, Recio FL, Rodriguez M, Olgaard K. Persistent downregulation of calcium-sensing receptor mRNA in rat parathyroids when severe secondary hyperparathyroidism is reversed by an isogenic kidney transplantation. J Am Soc Nephrol 2002;13(8):2110–6.
37. Canadillas S, Canalejo A, Santamaría R, et al. Calcium-Sensing Receptor Expression and Parathyroid Hormone Secretion in Hyperplastic Parathyroid Glands from Humans. J Am Soc Nephrol 2005;16(7):2190–7.
38. Lou I, Foley D, Odorico SK, et al. How Well Does Renal Transplantation Cure Hyperparathyroidism? Ann Surg 2015;262(4):653–9.
39. Cheng S-P, Lee J-J, Liu T-P, et al. Parathyroidectomy improves symptomatology and quality of life in patients with secondary hyperparathyroidism. Surgery 2014;155(2):320–8.
40. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis. J Am Soc Nephrol 2004;15(8):2208–18. 41. Danese MD, Kim J, Doan Q V, Dylan M, Griffiths R, Chertow GM. PTH and the risks for hip, vertebral,
42. Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int 2001;60(2):472–9.
43. Floege J, Kim J, Ireland E, et al. Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population. Nephrol Dial Transplant 2011;26(6):1948–55.
44. Pihlstrøm H, Dahle DO, Mjøen G, et al. Increased Risk of All-Cause Mortality and Renal Graft Loss in Stable Renal Transplant Recipients With Hyperparathyroidism. Transplantation 2015;99(2):351–9. 45. Parikh S, Nagaraja H, Agarwal A, et al. Impact of post-kidney transplant parathyroidectomy on
allograft function. Clin Transplant 2013;27(3):397–402.
46. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention and treatment of chronic kidney disease mineral and bone disorder (CKD-MBD). Kidney Int Suppl 2017;7:1–59.
47. Ngai M, Lin V, Wong HC, Vathsala A, How P. Vitamin D status and its association with mineral and bone disorder in a multi-ethnic chronic kidney disease population. Clin Nephrol 2014;82(4):231–9. 48. Gois PHF, Wolley M, Ranganathan D, Seguro AC. Vitamin D deficiency in chronic kidney disease:
Recent evidence and controversies. Int. J. Environ. Res. Public Health. 2018;15(8).
49. Nemeth EF, Steffey ME, Hammerland LG, et al. Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci U S A 1998;95(7):4040–5.
50. Greeviroj P, Kitrungphaiboon T, Katavetin P, et al. Cinacalcet for Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: A Meta-Analysis of Randomized Controlled Trials. Nephron 2018;139(3):197–210.
51. The Evolve Trial Investigators. Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis. N Engl J Med 2012;367(26):2482–94.
52. Mandl F. Therapeutischer Versuch bei einem Falle von Ostitis fibrosa generalisata mittels Exstirpation eines Epithelkorperchentumors. Zentralbl f Chir 1926;53:260.
53. Chen J, Jia X, Kong X, Wang Z, Cui M, Xu D. Total parathyroidectomy with autotransplantation versus subtotal parathyroidectomy for renal hyperparathyroidism: A systematic review and meta-analysis. Nephrology 2017;22(5):388–96.
54. Apetrii M, Goldsmith D, Nistor I, et al. Impact of surgical parathyroidectomy on chronic kidney disease-mineral and bone disorder (CKD-MBD) - A systematic review and meta-analysis. PLoS One 2017;12(11):e0187025.
55. Ma T-L, Hung P-H, Jong I-C, et al. Parathyroidectomy Is Associated with Reduced Mortality in Hemodialysis Patients with Secondary Hyperparathyroidism. Biomed Res Int 2015;2015:639587. 56. Hsu Y-H, Chen H-J, Shen S-C, Tsai W-C, Hsu C-C, Kao C-H. Reduced Stroke Risk After Parathyroidectomy
in End-Stage Renal Disease: A 13-Year Population-Based Cohort Study. Medicine (Baltimore) 2015;94(23):e936.
57. Rudser KD, de Boer IH, Dooley A, Young B, Kestenbaum B. Fracture Risk after Parathyroidectomy among Chronic Hemodialysis Patients. J Am Soc Nephrol 2007;18(8):2401–7.
58. Isaksson E, Ivarsson K, Akaberi S, et al. The Effect of Parathyroidectomy on Risk of Hip Fracture in Secondary Hyperparathyroidism. World J Surg 2017;41(9):2304–11.
