The circulating parathyroid hormone (PTH) secreted by the parathyroid glands performs the function of controlling both calcium and the skeletal metabolism. Generally, hypocalcemia and hyperphosphatemia are the classic stimuli for the secretion of PTH, whereas the active Vitamin D, 1,25-dihydroxy Vitamin D3 normally suppresses the secretion of PTH.  

Secondary hyperparathyroidism is a condition where there is a high level of parathyroid hormone secretion because of parathyroid hyperplasia caused by hyperphosphatemia, hypocalcemia, or decreased levels of active vitamin D. The high level of PTH will then increase the blood calcium by its effect on different organs affecting intestines, kidneys, and bones.  

Chronic SHPT is firmly associated with disturbances in the bone turnover rate and αvascular and visceral calcifications, which would contribute greatly to the causes of cardiovascular complications and increased mortality. Even with progress in medical treatments, most of these patients unfortunately end up needing surgery. This surgery usually becomes very vital, especially when the disease no longer responds to medical therapy. Renal transplantation can also salvage a few patients, unfortunately, does not reduce the hyperparathyroidism to zero. 

The most prevalent causes of CKD and vitamin D deficiency. Approximately 50% of the global population experiences vitamin D insufficiency. In the U.S.,around 15% of people are affected by CKD. In cases of CKD, elevated PTH levels are commonly observed, with a notable correlation between the severity of CKD and the increasing prevalence of elevated PTH, particularly in advanced stages of the disease.  

In SHPT, hypocalcemia stimulates the parathyroid to secrete PTH, resulting in parathyroid hyperplasia. Elevated levels of PTH increase calcium and phosphate absorption from the gut, stimulate the activity of osteoclasts, and enhance resorption of calcium and phosphorous from bone. In the kidneys, it activates PTH, increasing phosphate and calcium reabsorption in the renal tubules. Vitamin D suppresses PTH secretion while it regulates the levels of phosphorous and calcium. 

FGF-23 appears to contribute to phosphorous balance through increased phosphorous clearance in renal tubules, and the other by inhibiting the enzyme 1α-hydroxylase. The actions of FGF-23 on phosphate and vitamin D metabolism have indirect effects on PTH secretion. In CKD, decreased GFR results in an increase in PTH secretion and hyperphosphatemia. This imbalance causes hypocalcemia, which stimulates FGF-23 production, thereby further increasing PTH secretion. 

The common combination in which secondary hyperparathyroidism often presents is with deficits of CKD and vitamin D. In CKD, the kidneys cannot successfully transform vitamin D into its active form, 1,25-dihydroxyvitamin D. As such, calcium absorption in the gut is low, and calcium serum levels become low. At the same time, an inability of the kidneys to clear phosphate leads to high phosphate levels, further stimulating PTH secretion. Parathyroid hyperplasia is a result of persistent parathyroid stimulation. On other hand, secondary hyperparathyroidism may develop in vitamin D- deficient rickets, pseudohypoparathyroidism and malabsorption syndromes. 

Quality of life is affected by secondary hyperparathyroidism when there are complications such as mineral and bone disorders, heart diseases, and calciphylaxis. Consequently, fractures, pain in bone and muscle can affect everyday living to an extent. Although medical therapy aims at achieving KDOQI (Kidney Disease Outcomes Quality Initiative) guidelines for target levels, there is limited clinical evidence from prospective studies demonstrating that calcimimetics or vitamin D analogs improve survival. Nonetheless, calcimimetics have shown advantages in certain outcomes like decreased rates of fractures, parathyroidectomy as well as other quality of life improvements. 

Medical treatment resistant cases may undergo parathyroidectomy. Over time, the likelihood of undergoing parathyroidectomy increases among patients with end-stage renal disease (ESRD) on hemodialysis with approximately 15% of these patients having undergone this procedure within 5-10 years after starting dialysis. Parathyroidectomy regardless of the technique used significantly relieves most initial functional symptoms within a week after surgery but mild-to-moderate symptoms may persist during a six-month follow-up period according to studies. 

Because SHPT (secondary hyperparathyroidism) occurs to some degree in nearly all patients with CKD, there is no specific clinical presentation that distinctly identifies the condition. It is often picked up by routine laboratory tests done while monitoring patients with CKD. If secondary hyperparathyroidism occurs due to vitamin D deficiency, then the symptoms are primarily those of the vitamin deficiency itself, with an increased risk for fractures secondary to osteomalacia and rarely to myopathy. Some patients with more advanced cases of secondary hyperparathyroidism might also be found to have bone pain occasionally. 

SHPT is characterized by abnormal bone mineralization and remodeling. This could lead to skeletal deformities, thereby making these bone painful and deformed and even fractured in some severe cases. This aberrant remodeling and mineralization can lead to kyphoscoliosis and deformities of the chest wall, and the additional stress caused by the process of weight-bearing might lead to an added risk of fracture. Rickets in children may occur secondary to bone deformities because of SHPT. 

Extraosseous findings:  

There are also important extraosseous manifestations of secondary hyperparathyroidism. Calcifications can occur in various tissues, including internal organs, skin, arterial walls, and eye that includes the conjunctiva and cornea. These calcifications can contribute to severe itching, muscle weakness, and red-eye syndrome. Itching, especially common in advanced renal disease, is a result of phosphorous and calcium deposits on the skin. Further, calcifications may finally occur in the heart, including the mitral valve, myocardium, and aortic valve, probably paving an increased pathway for cardiovascular events to follow with left ventricular dysfunction, CHF, ischemia and death from arrhythmias. 

Calciphylaxis:  

This is a condition characterized by arterial obstruction leading to localized skin ulceration and necrosis of the extremities. The condition is due to most often elevated parathyroid hormone and secondarily, phosphorous or calcium, usually due to the high calcium content in phosphate binders and dialysate. The small venules and arterioles get calcified, with associated very prominent intimal hyperplasia, which may lead to painful skin necrosis and thrombosis. This highly increases the risk of infections, ischemia, sepsis and is related to increased mortality. 

Other findings may include neurological and psychological issues along with malnutrition. 

• Calciphylaxis 
• Non-healing wounds (chronic) 
• Enlargement of parathyroid glands 
• Worsening heart failure 
• Convulsions 
• QT prolongation 

Medical care:  

Treatment for SHPT usually involves medical therapy with vitamin D deficiency often addressed using ergocalciferol or cholecalciferol. For patients with CKD, the National Kidney Foundation recommends lowering the PTH levels to maintain normal bone turnover and reduce ectopic calcification. Non-surgical treatments include phosphate binders, restriction of dietary phosphorous, and calcimimetics such as cinacalcet. However, there is limited evidence supporting patient-based benefits of these. 

The latest medications such as cinacalcet and etelcalcetide work by binding to and activating the calcium-sensing receptor leading to a reduction in secretion of parathyroid hormone. Despite this, a study (EVOLVE trial) established that cinacalcet did not improve mortality or cardiovascular outcomes in individuals who were suffering from end-stage renal disease (ESRD). Although cinacalcet reduced the need for parathyroidectomy in refractory hyperparathyroidism cases, it also increased severe complications such as hypocalcemia among others. Still aggressive management of this patient population using cinacalcet did not result in improvement on cardiovascular outcomes nor mortality. 

 Surgical care: 

Parathyroidectomy is indicated in patients with severe hyperphosphatemia, hyperparathyroidism, or hypercalcemia unresponsive to medical therapy. Several studies have shown parathyroidectomy to decrease the risk of peripheral arterial disease in end-stage renal disease patients. It has been linked to a decrease in mortality in dialysis patients with severe secondary hyperparathyroidism. In addition, surgical intervention may improve quality of life, but these studies are all observational and include no randomized comparative data. 

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Dietary adjustments 

To manage hyperphosphatemia, patients should reduce the intake of phosphorous and ensure adequate calcium intake under medical supervision, avoiding high-phosphorous foods and beverages. 

Vitamin D supplementation 

Exposure to sun can boost the synthesis of vitamin D, but skin protection is crucial. Supplements like ergocalciferol or cholecalciferol may be necessary for those who are unable to obtain enough of it. 

Optimizing dialysis 

Adjusting composition of dialysis fluid and using phosphate binders effectively can help manage hyperparathyroidism by balancing the levels of phosphorous and calcium and alleviating increased secretion of PTH. 

Physical environment 

Ensuring safe living spaces and providing comfort and support are crucial for patients with weakened bones, preventing falls and fractures. 

Lifestyle modifications 

Regular exercise, physical therapy, and avoiding smoking and moderate alcohol can improve bone health, overall well-being, and treatment outcomes. 

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Phosphate binders that may be used to treat these include sevelamer carbonate, aluminum hydroxide, and lanthanum carbonate as well as sevelamer hydrochloride. Phosphate binders are divided according to composition into calcium-free and calcium-containing phosphate binders. Calcium-containing phosphate binders have been associated with an increased risk of soft and vascular tissue calcification and have been linked to reduced survival compared with calcium-free phosphate binders. 

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Cholecalciferol or vitamin D3, and ergocalciferol or vitamin D2 are the metabolites of vitamin D. Alfacalcidol, doxercalciferol, paricalcitol, and calcitriol from a pharmacological perspective, they are considered under the class of vitamin D receptor activators (VDRA). There is some evidence that suggests that vitamin D may confer survival benefits for patients with CKD. Analogues of vitamin D, have been associated with reduced levels of PTH and possibly other benefits in CKD, including reduced tubulointerstitial fibrosis, inhibition of renin-angiotensin system, reduced inflammation, protection from vascular calcification, and improved cardiovascular survival and outcomes. Although most of these results emanate from observational studies, more prospective randomized controlled trials are required to confirm such outcomes. 

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Calcimimetics such as etelcalcetide and cinacalcet act by increasing the sensitivity of calcium-sensing receptors in the parathyroid glands, thereby decreasing the production of PTH. These drugs decreased PTH without increasing either phosphorous or calcium. While not demonstrating improved survival or cardiovascular outcome, they demonstrated significant reductions in PTH, phosphate, FGF-23, and calcium levels. 

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Parathyroidectomy:  

This is a surgical option employed when medical treatments are ineffective or not sufficient. It is indicated for conditions such as calciphylaxis, refractory and severe pruritic, anemia unresponsive to erythropoietin, significant hypercalcemia, extraskeletal calcification, and levels of PTH exceeding 800pg/mL. Secondary hyperparathyroidism is marked by nodular hyperplasia and asymmetric enlargement of the parathyroid glands. Evaluating the parathyroid mass is essential for predicting how well the patient will respond to treatment. It is estimated that around 15% of patients will require surgery within 10 years, and about 38% within 20 years of starting dialysis. The use of calcimimetics has contributed to a reduction in the need for parathyroidectomy. 

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SHPT and Vitamin D deficiency are often associated with CKD. Both are frequently associated with associated with disrupted metabolism of phosphorous, vitamin D, and calcium leading to disorders in bone mineralization, calcification, and renal osteodystrophy in extraosseous sites such as coronary arteries. Early diagnosis and intervention in this disorder are very important. Medical treatment generally involves vitamin D analogs, phosphate binders, and calcimimetics. Early consultation with a nephrologist is important for proper management, and surgical intervention may be considered as a last resort if other treatments fail to provide adequate response.