Recent Advances in Treatment of Secondary Hyperparathyroidism in Chronic Kidney Disease

Ibrahim Khalil*¹, Mercy Zhou², Sadaf Noureen³, Damayanthi C Kulasena⁴, Nadeem Iqbal⁵
 

1. Shifa College of Medicine.

2. University of Tennessee Health Sciences Center:College of pharmacy.

3.The Groves Medical Centre New Malden.

4. Avalon University School of Medicine, Curacao.

5. PKLI, Lahore.

*Correspondence to: Dr. Nadeem Iqbal, Department of Urology and Kidney Transplant, Pakistan Kidney and Liver Institute Lahore, Pakistan Email:-dr_nadeemiqbal84@yahoo.com.

Copyright
© 2023: Dr. Nadeem Iqbal. This is an open access article distributed under the Creative Commons Attribution  License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original  work is properly cited.

Received:  19 December 2023

Published: 01 January 2024

DOI: https://doi.org/10.5281/zenodo.10486766

Abstract

Secondary hyperparathyroidism (SHPT) is the result of metabolic complications resulting from chronic kidney disease (CKD). In advanced stages of CKD  there is hyperphosphataemia along with hypocalcaemia which in turn leads to hypertrophy of parathyroid glands and excess production of PTH. The critical complications of SHPT encompass the skeletal and cardiovascular systems. That’s being the reason ,targeting pharmaceutically the levels of Hyperphosphataemia, controlling PTH hypersecretion and calcitriol deficiency and high serum FGF-23 levels can diminish the  accumulation of calcium salts inside the vascular wall and as such can mitigate the risk factors for cardiovascular related mortality in patients suffering from CKD.

Key Words:- CKD; kidney; treatment; bone mineral density; cardiovascular mortality.

Introduction

Secondary hyperparathyroidism (SHPT) is the result of metabolic complications resulting from chronic kidney disease (CKD). It is thought that  phosphate excretion by the kidneys deteriorates in CKD-2. (eGFR is 89–60 mL/min). This in turn results in  stimulation  of parathyroid cells ,produce elevated quantitiy of PTH, which in turn reduces phosphate reabsorption in the proximal tubule keeping serum phosphorus concentration within the normal range. However this compensation mechanism fails at CKD-4 (eGFR less than 30 ml/min). It results in hyperphosphataemia along with hypocalcaemia which in turn leads to hypertrophy of parathyroid glands and excess production of PTH. The critical complications of SHPT encompass the skeletal and cardiovascular systems. We have tried to summarise the major studies across the spectrum of chronic kidney diseases and developments in the treatment of secondary hyperparathyroidism.

Methods

We searched PubMed, and Medline database publications and results of clinical trials regarding the treatment for Secondary hyperparathyroidism during the last 10 years using: Secondary hyperparathyroidism , chronic kidney disease, treatments , metabolic bone disease. The publications included were special communications, reviews, books, and research presentations and studies regarding the subject matter over the years.

Discussion

Secondary hyperparathyroidism (SHPT) is one of the most common metabolic complications resulting from chronic kidney disease (CKD). The major complications of Secondary hyperparathyroidism include the skeletal and cardiovascular systems. Calcium and phosphate imbalances associated with CKD have been defined by the Kidney Disease Improvement Global Outcomes (KDIGO) group as chronic kidney disease-metabolic bone disease (CKD-MBD). These  can result in chronic pain syndromes and mobility problems, cardiovascular risks and above all increased mortality rates een in such patients [1, 2, 3].

Secondary hyperparathyroidism (SHPT) is often seen in the starting stages of CKD. Previously it was supposed that pivotal factors in the initatiation of SHPT are hypocalcaemia, hyperphosphataemia, and reduced calcitriol levels. Some new research has discovered new factors which could have an important role in the development of SHPT, namely Klotho protein deficiency and an increase in the serum concentration of fibroblast growth factor 23 (FGF-23) [4]. The end results of SHPT include mineral and bone disorders, such as renal osteodystrophy and blood vessels calcifications. This in turn can lead to cardiovascular manifestations and complications. In addition to this, muscle weakness, tendon ruptures, joint pain, bone fractures and, soft tissue calcification. Of all these, most dangerous complications is calcification in the cardiovascular system, resulting in significant mortality rates in those  with end-stage renal disease.

That’s being the reason, targeting pharmaceutically the levels of Hyperphosphataemia, controlling PTH hypersecretion and calcitriol deficiency and high serum FGF-23 levels can diminish the  accumulation of calcium salts inside the vascular wall and as such can mitigate the risk factors for cardiovascular related mortality in patients suffering from CKD [5-6].

Pharmacological treatment strategies for secondary hyperparathyroidism

There are two main types for treating  secondary hyperparathyroidism. The first is based on the use of drugs that lower serum phosphate levels, and the second is based on the suppression of PTH secretion by the parathyroid glands.

A. Medications that bind phosphate in the gastrointestinal tract: These are the most frequently prescribed to  patients suffering from advanced CKD. Medications that lower the serum phosphate level can be grouped as two subcategories:

1: calcium compounds, such as calcium carbonate or calcium acetate; and

2: non-calcium compounds, such as sevelamer hydrochloride or carbonate, lanthanum carbonate, aluminium hydroxide, and magnesium hydrochloride or carbonate.

There are some other new therapeutic options such as , iron preparations (ferric citrate, sucroferric oxyhydroxide, colestilan, or nicotinic acid amide) [7].

Calcium carbonate: It has been used most frequently among patients with CKD, including dialysis patients.Reason being, its low cost availability. It is pertinent to note that the daily intake of elemental calcium (intake in the diet plus the amount in phosphate binding preparations) should not cross above 1500 mg owing to the risk of hypercalcaemia, which in turn can cause calcification in soft tissues and blood vessels.Other than this , there is main concern of constipation as its side effect[8].

Non-calcium drugs: In one recent study it was deduced that  sevelamer, as a representative of non-calcium drugs, reduced all-cause mortality compared to calcium preparations. Additionaly, they found that iron-based drugs have a greater potency in terms of lowering serum phosphate concentrations when compared to other preparations [9]. Other studies have concluded  that sevelamer mitigated all-cause mortality when compared to calcium phosphate binders, however more  research studies on the efficacy of sevelamer are still required to draw  solid conclusions [10].

Iron preparations have been focused by many studies which drew results  of significant decrease in serum phosphate concentration after the utilization of ferric citrate. Not only this but also  the haemoglobin concentration increased significantly. It was noticed that iron citrate and sucroferric oxyhydroxide also decreased serum PTH levels [11].

Other pharmacological interventions have been explored such as colestilan (a non-absorbable resin that binds phosphate and bile acids in the intestine. However, this drug has shown significant gastrointestinal symptoms [12]. Risk benefit ratio studies regarding intervention to control phosphate levels and its relation to risk of death have mixed outcomes [13]. In important studies, in patients with CKD who are not on dialysis, the efficacy of drugs lowering blood phosphate levels is unsure, and more studies are required to ascertain their effectiveness in this group of patients.

On the other hand, in dialysis patients, research studies manifested a solid  relationship between serum phosphate levels and the risk of death [13]. There is strong evidence that phosphate overload shrinks  the survival of dialysis patients through unfavourable effects on the skeletal and cardiovascular systems [14]. However, studies have not indicated a reduction in mortality with phosphate binders compared to placebo even  including dialysis patients [15].

B. Drugs that inhibit the secretion of PTH by the parathyroid glands:

The second treatment strategy for Secondary hyperparathyroidism is to control serum PTH levels. The best level of PTH in CKD patients with stage G3-5 (who are not treated with dialysis) is still not understood. However, those who are on dialysis ,it is mostly recommended to  maintain the level of the hormone within the range of 2–9 times the upper limit of normal values (usually 140–600 pg/mL). Due to the risk of adynamic bone disease, in which there is reduced osteblasts and osteoclasts, no accumulation of osteoid and markedly low bone turnover, the  PTH levels should not  go down  below this range.

Following types of drugs are included in this type of treatment strategy.

1. Active vitamin D derivatives and its analogues (calcitriol, alfacalcidol, paricalcitol) and

2. Calcimimetics (cinacalcet) have been in use currently to diminish serum PTH levels [16-17].

Vitamin D analogues such as Paricalcitol and calcitriol have a similar suppressive effect on parathyroid cells. The most frequent side effects of paricalcitol are gastrointestinal symptoms including  rash, dizziness, elevated liver enzymes in blood [18].

Calcimimetics: Calcimimetics have been recognized as drugs of first choice for treating hypercalcaemia and uncontrolled hyperphosphataemia. They act on the parathyroid cells by inhibiting the secretion of PTH. Treatment with this is accompanied by a decrease in calcium and phosphate levels; therefore, periodicchecks of serum calcium levels is obligatory during treatment. The most frequent side effects is the gastrointestinal tract.There are other new medications compared with cinacalcet. For example,in one study it was deduced that  in dialysis patients using evocalcet and cinacalcet, evocalcet had good effectiveness in reducing serum PTH levels as cinacalcet,and it had lesser side effects [19]. More research is needed in the future so that cinacalcet will be replaced by newer drugs from the group of calcimimetics.

Recently intestinal microbiota are under under studies thatr in normal conditions have vital role in the fermentation of nutrients, and formation of bioactive particles such as vitamins and short-chain fatty acids (SCFA).New research shows relation of the intestinal microbiota to phosphate balance.However, the exact molecular mechanisms of these interesting processes are still unclear[20].In future more drugs will be tried targeting calcium and phosphate metabolism disorders accompanying chronic kidney disease.These will be ones that will stimulate the expression of Klotho protein or block FGF-23.

Conclusion

When treating seconadary hyperparathyroidismin chronic kidney disease ,it is vital to carefully select the available pharmaceutical treatment options.Different drugs will have variable side effects and efficacy to reduce the risk of chronic complications. In future more drugs  will be tried to reduce side effects and having more efficacy in this regard.

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