**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.

*Prognostic Value of Serum Parathyroid Hormone in Patients with End-Stage Renal Disease DOI: http://dx.doi.org/10.5772/intechopen.100229*

## **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.
