Prognostic Value of Serum Parathyroid Hormone in Patients with End-Stage Renal Disease

Abstract

End-stage renal disease (ESRD) is a clinical condition related to prolonged and irreversible loss of renal function. In addition to many others, it is associated with various disorders of calcium, magnesium and phosphorus metabolism which usually appears early in the course of the condition. Secondary hyperparathyroidism is a characteristic finding in patients with ESRD secondary to the previously mentioned metabolic abnormalities. The associated increase in plasma level of parathyroid hormone (PTH) has been correlated to many complications that accompany ESRD. These conditions might represent the major cause of mortality in certain circumstances. In light of this suggested impact of plasma level of PTH on many complications that are usually present in patients with ESRD, it might be of great benefit to regularly test this hormone in such patients.

1. Introduction

Calcium is one of the essential minerals in the human body being enrolled in various metabolic functions. About 99% of the total body’s calcium is present in bone, but the remaining fraction that is present in plasma or the intracellular compartment has a vital role in muscular contraction, normal blood coagulation system, cardiac muscle contractility and rhythm in addition to many other vital functions. Calcium homeostasis requires integration among various organs within the human body such as parathyroid glands, intestine and kidneys. In other words, normal concentration of plasma parathyroid hormone, intact absorptive function of the intestine, proper activation of vitamin D and normal renal re-absorptive and excretory function are all essential to maintain plasma calcium level within the reference range. In patients with chronic kidney disease (CKD), specifically those with advanced stage, there will be an associated progressive impairment of vitamin D activation due to progressive loss of nephrons. This will lead to significant malabsorption of calcium by the intestine with consequent hypocalcemia. This hypocalcemia, in addition to other factors, represents a major stimulus on parathyroid hormone (PTH) secretion by one of two mechanisms that are dependent on the duration of hypocalcemia. In the short term, hypocalcemia will stimulate PTH secretion via G-protein while prolonged hypocalcemia is associated with altered stability of m-RNA-encoding PTH. The pathophysiology of hypocalcemia in patients with chronic kidney disease is related to two main factors. First, the precipitation of calcium on various body tissues after being complexed with plasma phosphorus that is present in higher concentrations. Second, impaired absorption of calcium at the intestine secondary to the deficient active form of the vitamin (1,25 (OH)2 vitamin D) due to improper activation of vitamin D by the renal cortex. Because of the prolonged stimulation of parathyroid glands by the persistent hypocalcemia in patients with chronic kidney disease, secondary hyperparathyroidism will be an expected associated finding in such patients. So, secondary hyperparathyroidism will ensue with a consequent increase in plasma level of PTH. This condition is commonly encountered in patients with chronic kidney disease especially with advanced stages and has been proposed to be correlated with certain complications commonly seen in such patients including cardiovascular diseases and renal osteodystrophy. For this reason, the prognostic value of PTH in patients with chronic kidney disease has received great emphasis.

2. Secondary hyperparathyroidism

Next to vitamin D deficiency, chronic kidney disease is known to be the second most common cause of secondary hyperparathyroidism. The prevalence of secondary hyperparathyroidism in such patients is strongly correlated with the stage of CKD. In other words, plasma PTH concentration is negatively correlated with glomerular filtration rate (GFR) in patients with CKD. Around 80% of patients with GFR of less than 20 mL/min/1.73 m² has an increased level of PTH [1]. At the early stages of CKD, the major stimulus of the parathyroid glands is the hyperphosphatemia caused by impaired renal excretion of phosphorus in addition to impaired activation of vitamin D. Prolonged exposure to hyperphosphatemia and development of hypocalcemia in concurrence with high levels of fibroblast growth factor (FGF)-23 will lead to overproduction of PTH where hyperplasia of the parathyroid tissue ensues with persistent exposure to these metabolic abnormalities [2]. FGF-23 plays an indirect role in regulating the synthesis and secretion of PTH for being involved in regulating renal excretion of phosphate in addition to renal production of activated vitamin D. Furthermore, increasing studies suggest a direct role of FGF-23 in suppressing PTH synthesis and secretion through a direct action on the parathyroid glands. This inhibitory effect is significantly impaired in patients with CKD [3]. Persistent overstimulation of parathyroid glands is associated with hyperplasia that is categorized into 4 types which are diffuse hyperplasia, diffuse and multinodular hyperplasia, multinodular hyperplasia, and simple nodular hyperplasia [4]. Various clinical consequences are characteristic of secondary hyperparathyroidism including bone and soft tissue, skin and cardiovascular manifestations. Extraosseous calcification is the main pathophysiology of many clinical manifestations as it involves arterial walls, cutaneous tissue, viscera and even cornea and conjunctiva. This calcification is also correlated with the increased mortality rate in patients with CKD as it might involve myocardium and endocardium and the arterial walls of the aorta and coronary arteries leading to significant ventricular dysfunction, heart failure, ischemia, arrhythmia and death [5]. This might explain the increasing emphasis by many authors on serial measurement of plasma PTH in patients with CKD as a part of management.

3. Parathyroid hormone

Parathyroid hormone is an amino acid hormone composed of 84 amino acids, synthesized in the parathyroid glands. It is initially synthesized as pre-pro-PTH with 115 amino acids that is converted into pro-PTH with 90 amino acids. The latter will be cleaved to form the active form of PTH. The response of parathyroid glands to hypocalcemia by secreting PTH is so powerful. This response occurs within seconds of hypocalcemia in an attempt to rapidly restore normal plasma calcium levels. In addition to de novo synthesis, PTH is stored in secretory granules within the parathyroid glands and both represent the sources of circulatory PTH. The stored PTH within the parathyroid glands explains the rapid release of PTH from the parathyroid glands in response to short term hypocalcemia while prolonged hypocalcemia stimulates synthesis and release of PTH by parathyroid glands [6]. The estimated half-life of PTH is only a few minutes after which it is rapidly eliminated from circulation by the liver and kidneys [7]. The direct action of PTH involves three main organs; bone, kidneys and small intestine. In respect of its effect on the bones, PTH plays a vital role in releasing calcium to the circulation indirectly through the activation of osteoclasts (bone resorption). This action is preceded by stimulating the differentiation of osteoblasts into osteoclasts. This effect of PTH on the bones has a great impact on the rapid correction of plasma calcium levels in short-term hypocalcemia. On the kidneys, PTH has multiple functions that are essential in maintaining plasma calcium levels. At the distal convoluted tubules and collecting ducts, PTH mediates the reabsorption of calcium that has not been reabsorbed at the proximal convoluted tubules. Furthermore, PTH enhances the elimination of phosphate by decreasing the rate of its reabsorption, an action that is indirectly participating in maintaining plasma calcium as less phosphate will be available to bind with plasma free calcium [8]. Another vital action of PTH on the kidney includes increasing the production of 1 alpha-hydroxylase in the proximal convoluted tubules. The final step of activation of vitamin D is catalyzed by this enzyme. This active form of vitamin D mediates the absorption of calcium by the intestine in both transcellular and paracellular pathways in addition to its role in preventing loss of calcium in urine by enhancing its reabsorption at the distal convoluted tubules [9]. Currently, PTH is measured using the second generation intact PTH assay which has the ability to detect various PTH fragments including full-length (1–84) PTH and long C-PTH fragments, primarily (7–84) PTH, although the differences in the effects of each fragment on various systems in the body are not clear yet [10].

4. Correlation of parathyroid hormone and certain medical conditions

The higher incidence of certain medical conditions that have been observed in patients with high levels of plasma PTH has raised the suspicion of a possible role of PTH in the development of these conditions whether directly or indirectly. The indirect action is represented by alteration of plasma calcium concentration in form of hypercalcemia or hypocalcemia with their known impact on the function of various body organs. The direct action of PTH is related to its ability to bind to a G-protein-coupled receptor (PTH1R) leading to its activation with subsequent downstream activation of adenylyl cyclase and protein kinase A pathway or phospholipase C/protein kinase C (PKC) pathway according to the target organ [11]. This sequence of events when occurs within the cardiomyocytes will trigger further steps that end with excessive growth of cardiomyocytes and left ventricular hypertrophy [12]. The prevalence of hypertension in patients with primary hyperparathyroidism is extremely high reaching 40–60% [13]. Various mechanisms have been suggested for this correlation such as activation protein kinase C, exaggerated cardiovascular reactivity to norepinephrine, amplified effects of the renin-angiotensin system and many others [14]. Furthermore, altered glucose metabolism and even diabetes have been reported in patients with high plasma PTH concentration due to inhibition of insulin signaling in adipocytes via adenylate cyclase and phosphorylation of IRS-1 on serine 307 [15]. Approximately 8–22% of patients with primary hyperparathyroidism have type 2 diabetes mellitus and around 1% of patients with type 2 diabetes have primary hyperparathyroidism [16]. Although rare, acute pancreatitis has been as an initial presentation in patients with high plasma PTH levels due to a parathyroid gland tumor [17]. PTH has been correlated with metabolic syndrome, hyperlipidemia and coronary artery disease by many clinical studies [18, 19, 20]. For all this evidence, estimation of plasma PTH concentration should be a central step in the plan of management of many critical and highly prevalent medical conditions.

5. Plasma PTH level in patients with CKD

CKD is defined as progressive irreversible loss of renal function with associated metabolic disorders secondary to parenchymal renal damage. The severity of metabolic disorders associated with CKD is inversely related to glomerular filtration rate (GFR). Secondary hyperparathyroidism is an expected finding in patients with CKD caused by various factors related to impaired renal function including hyperphosphatemia, hypocalcemia and low levels of activated vitamin D. Consequently, persistently high levels of plasma PTH is an expected finding in patients with CKD. An important question is to determine whether this increase in PTH is considered an adaptive response or an exaggerated one. This has influenced some authors to calculate GFR-specific cutoff for PTH to differentiate between the two possibilities before considering PTH as a prognostic marker [21]. The major impact of PTH in patients with CKD is on bone metabolism and it is considered as the main cause for the development of mineral bone disease in such patients. Plasma PTH increases progressively at the early stages of CKD in an attempt to correct hyperphosphatemia. It is estimated that around 20% of patients with CKD have increased PTH concentration at GFR of more than 60 mL/min/1.73 m² compared to 40% at Stage 3, 70% at Stage 4, and > 80% at Stage 5 [22]. The role of PTH as a prognostic marker in patients with CKD was thoroughly studied and numerous studies have confirmed this role. For this reason, the National Kidney Foundation’s Kidney disease outcomes Quality Initiative (KDOQI) clinical practice guidelines recommend routine measurement of plasma PTH early in the course of CKD [23]. Furthermore, Kidney Disease Improving Global Outcomes (KDIGO) has recommended that PTH should be routinely checked in patients with CKD at stages 3–5 [24].

5.1 Prognostic value of plasma PTH in patients with CKD

Many deleterious consequences are known to be correlated with increased plasma PTH in patients with CKD including progressive deterioration of renal function, anemia, impaired response to erythropoietin in addition to many other medical conditions. The cardiovascular mortality rate is significantly increased even before reaching stage 5 [25]. This explains PTH being considered as a uremic toxin due to its extraskeletal effects [26]. These effects are thought to be related to the increase in intracellular calcium in various cells, apart from smooth muscle cells, secondary to a decreased efflux and an increased influx of calcium into the cells. Since the leading cause of death in patients with CKD is cardiovascular disease, the correlation between plasma PTH and cardiovascular disease in such patients has been reviewed thoroughly and it is worthy to start with this correlation when discussing the prognostic value of PTH in patients with CKD.

5.2 PTH and cardiovascular disease

It is well known that patients with end-stage kidney disease have an increased risk of cardiovascular disease of 5–10 times higher than the general population making it a challenge because it represents the major cause of death in such group of patients knowing that CKD represents a relatively highly prevalent medical condition where, in the USA, more than 50% of patients aged over 65 years have CKD [27]. The correlation between plasma PTH and the risk of all-cause and cardiovascular mortality has been confirmed when this risk was greatly reduced by parathyroidectomy. Various mechanisms have been implicated to explain this correlation. For example, cardiac sympathetic overdrive in addition to impaired vagal control in late stages of CKD was associated with arrhythmia which is responsible for sudden cardiac death in patients with CKD especially those on hemodialysis [28] which represents two-thirds of the total cardiovascular mortality in this group of patients. Altered cardiac autonomic modulation presented as decreased heart rate variability (obtained using 24-h Holter examinations) has been reported in patients with CKD and has been considered as a mortality risk predictor [29] where high plasma PTH was significantly correlated with decreased heart rate variability in patients with CKD on hemodialysis. Interaction between PTH and phosphorus, vitamin D and FGF-23 has been implicated in the development of this correlation [30]. Left ventricular cardiomyopathy represents the most frequent cardiac abnormality in patients on dialysis where left ventricular hypertrophy (LVH) is present in 60–75% of patients before initiating dialysis and up to 90% have LVH after dialysis. Although the pathophysiology of CKD-related cardiomyopathy is multifactorial, high plasma PTH is considered to have the main role in the development of this condition although other factors have been recently implicated including FGF-23 [31]. The findings during the histopathological study of post-mortem cardiac tissue were an increase in diameter of cardiomyocytes, reduced density of capillary length and an increase in interstitial volume [32]. Furthermore, diffused interstitial fibrosis has been observed in cardiac tissue in advanced cases of CKD and has been partially linked to PTH among other factors [33]. Many clues are present about the vascular effect of PTH and its association with hypertension and stroke. In respect to the correlation of PTH and hypertension in patients with CKD, elevated blood pressure has been normalized in patients on hemodialysis when treated with parathyroidectomy [34, 35] or etelcalcetide [36]. On the other hand, certain studies have revealed a strong predictive value of PTH and ischemic stroke especially in the presence of 25 (OH)D. The latter seems to have the highest predictive value even when compared to hypertension and high PTH [37]. In addition, increasing attempts are present to determine a reliable biomarker that can detect patients with CKD who have a higher risk of cardiovascular mortality. So, in addition to the conventional biomarkers, PTH and phosphorus, newer ones such as FGF23, Klotho, and sclerostin might have a slightly better prognostic value. In respect to FGF23, it is thought to represent a biomarker of the bone-heart axis as it might be a link between bone metabolism and cardiac function [38]. A higher concentration of circulating FGF-23 has been correlated with an increased risk of cardiovascular disease in patients with CKD where LVH and heart failure were significantly higher [39]. Various clinical studies have suggested that a progressive increase of circulating FGF-23 in patients with CKD was associated with a significant increase in all-cause mortality [40, 41]. Similarly, soluble klotho, co-receptor for FGF-23, has been investigated for its correlation with morbidity and mortality in patients with CKD. It has been shown that the prevalence of cardiovascular events was much higher in patients with low klotho concentration irrespective of other predictors of cardiovascular disease in patients with CKD [42]. Furthermore, low serum klotho has been associated with higher all-cause mortality even after adjustment of other confounders [43].

It is worthy to mention that even in the presence of normal renal function, high plasma PTH levels are associated with increased risk of coronary artery disease and heart failure [44] but this correlation requires further studies as certain authors have not confirmed it.

5.3 PTH and anemia

Anemia is a highly prevalent finding in patients with CKD and is considered as a sign of poor prognosis as it is associated with increased cardiovascular disease, hospitalization and mortality. Up to 100% of patients with stage 5 KCD have anemia. It is of a different pathophysiological basis although erythropoietin deficiency is the most recognized underlying cause. Other causes include resistance to erythropoietin, bone marrow fibrosis and shortened life span of red blood cells [45]. Secondary hyperparathyroidism and the associating high PTH level have been linked to these suggested causes of anemia. Bone marrow fibrosis has been detected in both primary and secondary hyperparathyroidism with consequent anemia which is significantly improved after parathyroidectomy making the correlation of bone marrow fibrosis and secondary hyperparathyroidism highly suggestive [46, 47]. Fortunately, bone marrow fibrosis has been reversed after parathyroidectomy. The direct inhibitory effect of PTH on erythropoietin synthesis has been confirmed by many authors when plasma concentration of erythropoietin increased significantly after parathyroidectomy reaching to 10-folds higher than its preoperative concentration within 2 weeks or even less; the molecular pathophysiology of this inhibitory effect is not yet known [48, 49]. Shortened lifespan of red blood cells has been observed in patients with CKD as a cause of anemia and it was linked to the high plasma PTH due to its role in increasing median osmotic fragility of red blood cells with consequent anemia [50]. Cinacalcet hydrochloride, a calcimimetic drug, which is used as a medical treatment of secondary hyperparathyroidism has been associated with improvement in hemoglobin level and necessitating fewer doses of erythropoiesis-stimulating agents to correct anemia [51, 52]. Similarly, patients with CKD and secondary hyperparathyroidism treated with the active form of vitamin D (calcitriol) have shown a similar response to that of cinacalcet with improved hemoglobin level and less doses of erythropoietin required to control anemia [53].

5.4 PTH and mortality rate in patients with CKD

The triad of altered calcium and phosphorus metabolism and high plasma PTH level represents one of the major challenges during the management of patients with CKD due to their adjuvant harmful consequences on various body tissues and their correlation to the high mortality rate commonly observed in patients with CKD with the leading cause being the cardiovascular disease. These disorders of metabolism are associated with accelerated vascular calcification involving various arteries including coronary arteries. Both hypercalcemia and hyperphosphatemia that are present in patients with prolonged secondary hyperparathyroidism seen in patients with CKD are associated with medial calcification. Furthermore, skin and soft tissue necrosis and ulceration, known as uremic arteriolopathy or calciphylaxis, is an uncommon serious complication of secondary hyperparathyroidism and has an eight-fold increase in mortality [54]. Many studies have suggested PTH as an independent risk factor for renal death in patients with CKD whether on renal replacement therapy or not [55, 56]. The severity of increase of PTH prior to hemodialysis has been shown to predict more difficulty in decreasing PTH afterwards [57]. It is of great importance to notify that a low or even normal concentration of PTH is thought to be associated with poor prognosis as well. KDIGO recommend plasma concentration of PTH to be 2–9 times the upper normal limit [57]. A gradual decrease of PTH to the target level has been associated with a significant decrease in mortality rate. Patients with concomitant high plasma concentrations of PTH and phosphorus have shown a higher risk of mortality [58]. The residual renal function seems to be a determinant factor for the risk of mortality in patients with high plasma PTH. Many clinicians are attracted to normalize PTH using various modalities including vitamin D, phosphate binders and calcimimetics but their benefit in reducing the mortality rate is questioned depending on various clinical studies that failed to confirm an association between the improvement in biochemical and hematological parameters and reduction of the risk of mortality rate suggesting more precautions for the use of these modalities in an attempt to reduce the risk of renal death [59]. In contrast, a recent meta-analysis study enrolling around 25000 patients has suggested a significant beneficial effect of parathyroidectomy in reducing mortality rate explained by controlling blood pressure and improvement of left ventricular hypertrophy [60].

All these findings highlight the importance of plasma PTH in the management of patients with CKD making it a cornerstone in the course of the illness as it affects various tissues and organs in the body in addition to its confirmed correlation with the risk of mortality in such patients.