secondary hyperparathyroidism in patients with …Ÿırı paratiroid hormon düzeyleri (pth),...

256 Şişli Etfal Hastanesi T›p Bülteni, Cilt: 50, Say›: 4, 2016 / The Medical Bulletin of Sisli Etfal Hospital, Volume: 50, Number 4, 2016

Secondary Hyperparathyroidism in Patientswith Chronic Kidney Disease: Diagnosis,Pharmacological and Surgical Treatment

Mehmet Uludag1

Review / Derleme DOI: 10.5350/SEMB.20161223024725

1Sisli Hamidiye Etfal Training and Research Hospital, Department of General Surgery, Istanbul - Turkey

Address reprint requests to/ Yazışma Adresi:Mehmet Uludağ,Sisli Hamidiye Etfal Training and Research Hospital, Department of General Surgery, Istanbul - Turkey

Phone / Telefon: +90-212-373-5000

E-mail / E-posta:[email protected]

Date of receipt / Geliş tarihi:December 11, 2016 / 11 Aralık 2016

Date of acceptance / Kabul tarihi:December 15, 2016 / 15 Aralık 2016

ABSTRACT:Secondary hyperparathyroidism in patients with chronic kidney disease: Diagnosis, pharmacological and surgical treatment Secondary hyperparathyroidism (SHPT) is a secondary adaptive response to maintain calcium homeostasis and caused by any condition associated with chronically reduced serum calcium (Ca) levels, and low serum Ca levels lead to compensatory overactivity of the parathyroid gland. It is a common complication of chronic kidney disease (CKD) and is part of the CKD-mineral bone disorder (CKD-MBD). SHPT is associated with increased risk of morbidity and mortality; thus, SHPT control is recommended. SHPT develops in patients with CKD due to a variety of mechanisms including increased phosphorus and fibroblast growth factor 23 (FGF23), and decreased calcium and 1.25-dihydroxyvitamin D levels. Patients present with various bone disorders, cardiovascular disease, and certain patterns of biochemical abnormalities. The diagnosis of patients with SHPT require a combination of clinical investigation and laboratory findings. Many patients with this disease are asymptomatic and only have abnormalities detectable by laboratory and radiologic studies. Laboratory tests may reveal hypocalcemia, normocalcemia or hypercalcemia and hyperphosphatemia. In addition, patients wirh SHPT have extremely elevated parathyroid hormone (PTH) levels, elevated or normal alkaline phosphatase (ALP) levels and decereased vitamin D (vit D) levels. Patients also can become symptomatic. Untreated SHPT leads to progressive bone disease, osteitis fibrosa cystica, and soft tissue calcifications. Patients may experience intractable bone pain, fractures, pruritis, soft tissue or vascular calcifications, calciphylaxis, erythropoietin resistant anemia, and mental status changes.Medical treatment consists of controlling hyperphosphatemia, vit D analogs and Ca administration, and calcimimetic agents. The majority of patients with SHPT can be managed by medical treatment. Despite improvements in medical therapy, it does not always provide control of the SHPT. Some patients require surgical treatment. The surgical indications include PTH levels >500-800 pg/ml associated with hypercalcemia and/or hyperphosphatemia despite medical therapy. Other indications include calciphylaxis, fractures, bone pain or pruritis. Pre-operative imaging is only occasionally helpful except in re-operative parathyroidectomy (PTX). Operative approaches include subtotal PTX, total PTX (TPTX) with or without autotransplantation, and possible thymectomy. Each approach has its own proponents, advantages and disadvantages which are discussed. Hypocalcemia is the most common postoperative complication requiring aggressive calcium administration. Benefits of surgical treatment may include improved survival, bone mineral density and alleviation of symptoms.Keywords: Chronic kidney disease, parathyroidectom, secondary hyperparathyroidism

ÖZET:Kronik böbrek hastalıklı hastalarda sekonder hiperparatiroidizm: Tanı, medikal ve cerrahi tedaviSekonder hiperparatiroidizm (SHPT) serum kalsiyum (Ca) düzeylerinin kronik düşüşü ile ilgili herhangi bir durum tarafından neden olunan ve Ca dengesini sürdürmek için sekonder adaptif cevaptır. Düşük serum Ca düzeyleri para-tiroid bezlerinin kompansatuar aşırı aktivitesine yol açar. SHPT kronik böbrek hastalığının sık bir komplikasyonudur ve kronik böbrek hastalığının mineral kemik bozukluklarının bir parçasıdır. SHPT artan mobidite ve mortalite riski ile ilişkilidir, bu nedenle SHPT’nin kontrolü önerilir. SHPT kronik böbrek hastalıklı hastalarda artan fosdor ve fibroblast büyüme faktörü 23 (FGF23), düşen Ca ve 1.25 dihidroksivitamin D3 düzeylerini içeren değişik mekanizmalaradan dolayı gelişir. Hastalarda değişişik kemik bozuklukları, kardiyovasküler hastalık ve belirli biyokimyasal anormallikler vardır. SHPT’li hastaların tanısında klinik inceleme ve laboratuvar bulgularının kombinasyonu gerekir. Birçok hasta asemptomatiktir ve sadece laboratuvar ve radyolojik çalışmalarla saptanabilen anormalliklere sahiptir. Laboratuvar testleri, hipokalsemi, normokalsemi veya hiperkalsemi ve hiperfosfatemi gösterebilir. Ek olarak SHPT’li hastalar, aşırı paratiroid hormon düzeyleri (PTH), artmış veya normal alkalin fosfataz (ALP) seviyeleri ve azalmış vitamin D (vit D) düzeylerine sahiptir. Hastalar semptomatik hale gelebilir. Tedavi edilmeyen SHPT, ilerleyici kemik hastalığı, osteitis fibroza sistika ve yumuşak doku kalsifikasyonlarına yol açar. Hastalar; dirençli kemik ağrısı, kırıklar, kaşıntı, yumuşak doku veya vasküler kalsifikasyonlar, kalsifilaksi, eritropoietine dirençli anemi ve zihinsel durum değişiklik-leri yaşayabilir. Medikal tedavi hiperfosfateminin kontrolü, vit D analogları, Ca uygulaması ve kalsimimetik ajanları içerir. SHPT’li hastaların çoğunluğu tıbbi tedavi ile tedavi edilebilir. Medikal tedavideki gelişmelere rağmen, mrdikal tedavi ile SHPT’nin kontrolü her zaman sağlanamaz. Bazı hastalarda cerrahi tedavi gerekir. Cerrahi endikasyonlar medikal tedaviye rağmen hiperkalsemi ve / veya hiperfosfatemi ile ilişkili 500-800 pg/ml’den yüksek PTH düzeyle-rini içerir. Diğer endikasyonlar kalsifiklaksi, kırıklar, kemik ağrısı veya kaşıntıdır. Preoperatif görüntüleme reoperatif paratiroidektomi (PTX) haricinde nadiren yardımcıdır. Operatif yaklaşımlar, subtotal PTX, ototransplantasyonlu veya ototransplantasyonsuz total PTX (TPTX) ve olası timektomiyi içerir. Her yaklaşımın önerileri, avantajları ve dezavan-tajları tartışılmıştır. Hipokalsemi, agresif Ca uygulaması gerektiren en yaygın postoperatif komplikasyondur. Cerrahi tedavinin faydaları, sağ kalım artışı, kemik mineral yoğunluğu artışı ve semptomların hafifletilmesini içerebilir.Anahtar kelimeler: Kronik böbrek hastalığı, paratiroidektomi, sekonder hiperparatiroidizm

Ş.E.E.A.H. Tıp Bülteni 2016;50(4):256-72

Şişli Etfal Hastanesi T›p Bülteni, Cilt: 50, Say›: 4, 2016 / The Medical Bulletin of Sisli Etfal Hospital, Volume: 50, Number 4, 2016 257

M. Uludag

INTRODUCTION

Secondary hyperparathyroidism (SHPT) is a secondary adaptive response to maintain calcium homeostasis and caused by any condition associated with chronically reduced serum calcium (Ca) levels, and low serum Ca levels lead to compensatory overactivity of the parathyroid gland. Chronic kidney disease (CKD) is the common cause of SHPT. Furthermore, other diseases, including inadequate dietary Ca intake, steatorrhea, and vitamin D (vit D) deficiency can produce this condition (1). SHPT is present in the majority of dialysis patients with end-stage CKD and is part of the CKD-mineral bone disorder (CKD-MBD) in this population. Physiologic manifestations of SHPT include increase in bone turnover that leads to increased bone and muscle pain, weakness, and fractures. Severe SHPT leads to pruritus, calciphylaxis, and neuromuscular disturbances, thus contributing to poor health-related quality of life in dialysis patients (2). Fur thermore, observat ional s tudies have demonstrated that elevations in serum Ca, phosphorus (P), and parathyroid hormone (PTH) levels are associated with increased cardiovascular and all-cause mortality (3). Primary care providers need to be aware of the pathogenesis and pathophysiology of SHPT and should be able to screen for, diagnose, and treat this complication (4). Among patients with CKD, the stages are defined based on the level of kidney function. The Kidney Disease Outcomes Quality Initiative (KDOQI) from the National Kidney Foundation (NKF) in 2002 released guidelines that stratified CKD into five stages (Table-1) and summarized complications, treatment, and other

management strategies related to each stage (5). The guidelines were most recently updated in 2012 (6). Most complications of CKD begin to be symptomatic or evident in serum markers in stage 3 (estimated glomerular filtration rate (eGFR) falls to 60 mL/min/1.73 m2 or lower). Before that, even as nephrons are injured or destroyed, individuals have adequate glomerular filtration rate (GFR) and physiological function, and the nephrons begin to hyperfilter as they try to compensate for their declining numbers. The patient remains asymptomatic and unaware of loss of kidney function, even as GFR falls and serum creatinine begins to rise above normal (4). The majority of patients with SHPT can be managed by medical t reatment. Despite improvements in medical therapy, it does not always provide control o f the SHPT. Surgical parathyroidectomy (PTX) is required in about 15% of patients receiving dialysis for more than 10 years, and in about 38% of patients receiving dialysis for more than 20 years (7). Because SHPT is a compensatory mechanism of the parathyroid glands, it commonly resolves with normalization of Ca and P homeostasis after renal transplantation (8). This review aims to give an overview on the pathophysiology, biochemical and clinical findings, medical and surgical treatment for SHPT in CKD including some of the limitations of current therapeutic options.

CALCIUM AND PHOSPHORUS HOMEOSTASIS (Figure-1)

Calcium and P homeostasis is largely regulated through a complex relationship between the bones,

Table-1: Stages of Chronic Kidney Disease (GFR: Glomerular filtration rate)

Stage DescriptionGRF(mL/min/1.73 m2)

1 Kidney damage with normal or ↑ GFR > 902 Kidney damage with mild ↓ GFR 60-893 Moderate ↓ GFR 30-594 Severe ↓ GFR 15-295 Kidney failure <15 (or dialysis)

Chronic kidney disease is defined as either kidney damage or GFR <60 mL/min/1.73 m2 for ≥3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies (5)

Secondary hyperparathyroidism in patients with chronic kidney disease: Diagnosis, pharmacological and surgical treatment


intestine, kidneys, and parathyroid glands (8). Calcium is the fifth most common element in human beings, with a body content of ∼1000 g in adults. It plays a key role in skeletal mineralization, as well as a wide range of biological functions (9). The vast majority of total body Ca (>99%) is present in the skeleton as calcium-phosphate complexes, primarily as hydroxyapatite, which is responsible for much of the material properties of bone (10). In bone, Ca serves two main purposes: it maintains skeletal strength and, concurrently, provides a dynamic store to maintain the intra- and extracellular Ca pools (9). Non-bone Ca represents <1% of total body Ca stores (∼10 g in an adult). Calcium is the most abundant cation in the human body, and plays a critical role in intracellular and extracellular events in human physiology. Extracellular Ca levels are about 10000 fold higher than intracellular levels and both are tightly controlled within a narrow physiological range to provide for proper functioning of many tissues. Intracellular Ca is an important second messenger regulating cell division, cell motility, membrane trafficking, secretion, and muscle contractility. Extracellular Ca is important for excitation-

contraction coupling in the heart and other muscles, synaptic transmission and other functions of the nervous system, coagulation, platelet aggregation, secretion of hormones and other regulators by exocytosis. (11,12). The total serum Ca ranges from ∼8.8 to 10.4 mg/dl (2.2 to 2.6 mM) in healthy subjects. Approximately 50% of serum Ca is in the ionized form, representing the active component (11). The remainder is bound to albumin (∼40%), or complexed with organic anions such as phosphate and citrate (∼9%) (9,11,12). Extracellular and serum Ca concentrations are closely regulated within a narrow physiological range that is optimal for many cellular functions. The primary Ca regulating hormones in humans are PTH and vitamin D. These modulate Ca levels via their effects on target organs such as the bone, kidney, and gastrointestinal tract. The average diet contains about 1 g of Ca, but there is a wide variation. About 500 mg is absorbed from the diet. Approximately 10000 mg/day is filtered at the glomerulus and most is reabsorbed by the renal tubules, with only a few hundred mgs appearing in urine each day. The skeleton turns over about 250 mg/day of Ca, with a wide variation (13).

Figure-1: Flowchart showing the calcium homeostasis (PTH: Parathyroid hormone, P: Phosphorus, Ca: Calcium, 25 OH vitD: 25-dihydroxyvitamin D, 1,25 (OH)2 vitD: 1.25-dihydroxyvitamin D (Active vitamin D –calcitriol-), (+): positive effect, (-): negative effect


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Phosphorus is more widely distributed than Ca and also serves a variety of biological functions. While most of P is skeletal as hydroxyapatite, 15% is distributed among extraskeletal sites like phosphoproteins, phospholipids, and nucleic acids. In blood, P concentration ranges between 2.5 and 4.5 mg/100 ml in healthy subjects. The regulation is not as strict as it is for Ca, with substantial perturbations due to diet (13). Dietary P comes mostly from foods, with an average of about 1 g/day. Absorption begins at a site distal to duodenum, utilizing both Ca-dependent and Ca-independent mechanisms that can be active or passive. Quantitatively, the most significant is the post-prandial passive absorption. Approximately 60-80% is absorbed primarily by a diffusional process without a significant saturable component; however, there is regulation by the calciotropic hormones, especially vitamnin D (vit D), whose active metabolites increases absorption, while PTH has only minor direct effects (13,14). Renal phosphate reabsorption controls the

concentration of phosphate in serum, and it is usually quantified as the tubular reabsorption of P and expressed as the renal phosphate threshold. The proximal convoluted tubule reabsorbs about 75% of filtered phosphate, and most of the remainder is reabsorbed in the proximal straight tubule; the distal tubule segments may have a limited capacity for reabsorption (13). The parathyroid cells rely on a G-protein coupled membrane receptor, designated as the Calcium-sensing receptor (CaSR), to regulate PTH secretion by sensing extracellular Ca levels. PTH is initially synthesized as a 115-amino acid precursor (pre-pro-PTH) that is subsequently followed by the final 84-amino acid molecule secreted by the parathyroid chief cells in response to a decrease in serum Ca levels. It acts on target organs by binding to and activating one of several types of PTH receptors. PTH increases the bone resorption by stimulating osteoclasts and promotes the release of Ca and P into the circulation. In kidney, PTH receptor binding leads to increased

Figure-2: Flowchart showing the pathophysiologic basis for secondary hyperparathyroidism (PTH: Parathyroid hormone, P: Phosphorus, Ca: Calcium, Pt: Parathyroid, FGF23: Fibroblast growth factor-23, CaSRs: Calcium sensing receptors, 1,25 (OH)2 vitD3: 1,25-dihydroxyvitamin D (active vitamin D –calcitriol-) (4)



Ca reabsorption and increased activity of renal 1-alpha hydroxylase, which converts 25-(OH) vit D to 1.25-(OH)2 vit D3 (calcitriol), and inhibited P reabsorption. 1.25-(OH)2-vitD3 (calcitriol) is the most metabolically active form of vit D. Vit D increases the absorption of Ca and P from the intestine and the resorption of Ca from the bone (11). An important role of fibroblast growth factor 23 (FGF23) in phosphate metabolism has been elucidated. This glycoprotein product of osteocytes and osteoblasts acts physiologically in the kidney to induce phosphaturia and inhibit the synthesis of 1.25-(OH)2-vit D3. The expression of FGF23 is upregulated by serum phosphate and 1.25-(OH)2-vit D3. In addition, PTH acts directly on osteocytes to increase FGF23 expression (13,15).

PATHOPHYSIOLOGY OF SECONDARY HYPERPARATHYROIDISM IN CHRONIC KIDNEY DISEASE (Figure-2)

The pathological mechanisms of SHPT are complex and incompletely understood. The primary known stimulus for PTH secretion is low serum Ca, and persistently low serum Ca measurements may well be expected in patients with SHPT. However, patients with CKD and SHPT often have normal serum Ca levels or between low-normal range, which demonstrates that more complex biochemical interactions are at play (16). At least four interdependent components that affect Ca homeostasis contribute to the development and progression of SHPT (Table-2). Impaired urinary phosphate excretion and hyperphosphatemia, along with decreased renal production of 1.25-(OH)2-vit D3 have been implicated in the reduction of functions of nephrons in CKD. Hyperphosphatemia contributes to hypocalcemia by binding to ionized Ca in the serum as Ca-phosphate and by directly inhibiting renal 1-alpha hydroxylase. Reduced 1.25-(OH)2 vit D3 levels contributes to SHPT by direct hypocalcemia and activation of PTH synthesis by vit D receptor (VDR) on parathyroid cells (14,17,18). However, recent data have indicated the important role of the FGF23 in CKD and subsequently in SHPT. FGF23 levels start to rise in early CKD stage

2 (Table-2), prior to elevations of phosphate and PTH. FGF23 maintains normal serum phosphate via two 2 main mechanisms (17,18). FGF23 decreases phosphate reabsorption in the proximal tubules and reduces 1.25(OH)2 vit D3 levels through decreased expression of 1-alpha hydroxylase (19). The net effect is a decrease in 1.25(OH)2 vit D3 level which reduces Ca and P absorption from the intestine (14). Serum P level is sustained in the normal range until the phosphaturic effect of FGF23 is blunted due to the diminished number of nephrons with progressive CKD (18). FGF23 also has an inhibitory effect on PTH secretion, though given the potential for extremely high levels of PTH in endstage CKD the importance of this effect is not clear (17). High circulating FGF23 is associated with worse patient outcome and reduced survival, as well as diminished PTH response to vit D or vit D analog treatment (17). In patients with CKD, PTH is elevated as a result of decreased serum Ca, 1.25- (OH)2 vit D3 deficiency, phosphate retention and elevated FGF23, in addition to the diminished expression of VDR and CaSR in the parathyroid cells. Therefore, SHPT in CKD develops due to a combination of these factors (14,17,20). In patients with CKD, persistent stimulation of the parathyroid glands due to hyperphosphatemia, low 1.25 (OH)2 vit D3 and intermittent hypocalcemia leads to diffuse (polyclonal) hyperplasia which transforms into nodular hyperplasia (monoclonal) (18). The glands develop nodular hyperplasia with several nodules in which parathyroid cells proliferate monoclonally with high growth potential, but express significantly less VDR and CaSR (20). Thus, they may become autonomous and unresponsive to negative feed-back mechanisms such as elevated serum Ca levels and administration of calcitriol (17,20). PTH release becomes autonomous which

Table-2: Factors that contribute to the development and progression of SHPT

Factors

1. Hyperphosphatemia2. Hypocalcemia3. Impaired vit D activation4. Increase fibroblast growth factor- 23 expression


M. Uludag

often results in hypercalcemia and termed tertiary hyperparathyroidism. Tertiary hyperparathyroidism generally occurs in a subset of patients with SHPT frequently manifesting after renal transplantation (17).

DIAGNOSIS

The diagnosis of patients with SHPT requires a combination of clinical and laboratory investigations.

Clinical Presentation (Table-3)

As described under the title of physiopathology in chronic CKD, mineral metabolism disorders related to Ca, P, magnesium (Mg), PTH and vit D metabolism are common. These abnormalities, as well as other factors related to the uremic state affect the skeleton. Traditionally, diseases related to these have been considered as bone lesions in the past and bone-related findings have been defined as renal osteodystrophy. However, recent evidence suggests that mineral abnormalities play an important role also in the pathogenesis of non-skeletal calcifications and result in vascular calcification and cardiovascular complications and mortality. It is defined as mineral and bone disorders in CKD to describe this broad pathological spectrum involving both bone findings and other findings. Mineral and bone disorders in CKD are associated with wide biochemical and clinical disorders (20,21). Their effects cause vascular calcification and bone abnormalities (17). This wide clinical syndrome results in cardiovascular disease, fracture, decreased quality of life and mortality as a

result of these underlying pathological developments. Many patients are asymptomatic with today’s medical treatments. In general, abnormalities are detected in the laboratory and radiological examinations before clinically significant pathology is detected. Present symptoms are also non-specific, sometimes with specific symptoms and signs. Bone pain is a common finding in patients with CKD with advanced bone involvement. It is usually insidious, and aggravated with changing the position of the body or depending on the weight of the body. Depending on the body weight, there is pain in the lower back, hips and legs. Metabolic bone diseases in patients with CKD are referred to abnormalities in bone turnover, mineralization and volume, which are quantifiable by bone biopsy (23). Bone turnover may be classified as either low (osteomalacia, adynamic bone disease), high (osteitis fibrosa cystica), or a combination of both high and low states (mixed uremic osteodystrophy). A high turnover state, characterized by increased bone formation and resorption, is seen in SHPT. Low-turnover bone disease is commonly observed in patients with kidney disease, especially in dialysis patients, and is characterized by an extremely slow rate of bone formation. Some cases demonstrate osteomalacia, which is characterized by defective bone mineralization in addition to the very slow bone formation rate. The osteomalacic lesion is mostly due to aluminum accumulation and is less common nowadays with the decreased usage of

Table-3: Clinical findings of secondary hyperparathyroidism

• Asymptomatic• Symptoms and signs of skeletal muscle

- Bone pain- Proximal muscle weakness- Bone lesions

• Osteitis fibrosa cystica (subperiosteal erosion)• Brown tumor• Pathological fracture

• Soft tissue calcifications• Vascular calcifications• Calciphylaxis

Figure-3: It is characterized by the subperiostal bone loss of osteitis fibrosa cystica in 2nd phalanges



aluminum-containing phosphorus binders (21). Some patients will have evidence of more than one type (17). A similar set of symptoms may be seen in both the low and high-turnover types of skeletal abnormality (22). The pain may be present rarely in knee, ankle and heel. Acute localized pain may also be present rarely, suggesting acute arthritis. It is the result of accumulation of calcium-phosphate crystals arount the joint, causing periarthritis, in particularly patients with hyperphosphatemia. The symptoms may be confused clinically with other forms of arthritis such as gout or pseudogout (22). Proximal myopathy may be prominent in advanced CKD. It is difficult to climb up to a high chair org et up from a low chair. Subperiosteal erosions are often present in severe SHPT (Figure-3). The grade of subperiosteal erosion is correlated with serum ALP and PTH levels. However, intermediate or severe fibrosa cystica findings can be detected in biopsy in patients with normal radiological findings. These findings can be best seen in the second phalanges in the hand x-ray (Figure-3). It may also be present at the distal end of the clavicle, pelvic ischium and pubic arm, in the sacroiliac joint and in the metaphysis-diaphysis junction of long bones. Focal radiolucent areas and frosted glass appearance are detected in the craniograph. Osteosclerosis may be present in the vertebrae (11). Brown tumor is the focal accumulation of the giant cells. It is typical for severe HPT. They are

usually seen as well-defined radiolucent areas in the long bones, clavicle and hands (Figure-4). It can be mixed with osteolytic metastases. Missing areas (looser zones) or pseudofractures are characteristic for osteomalasia. Routine skeleton films are not recommended (23). Non-skeletal calcifications are common findings in patients with advanced CKD. Non-skeletal calcifications can be classified as visceral, vascular and periarticular (16,17,22). The most common is the vascular calcifications (Figure-5). Although atherosclerotic calcifications are seen in the vascular intima, uremic calcifications are seen in the tunica media layer. This type of calcification is related with the reduction of the distension of blood vessels. This may cause lead pile sign pathologically and is related with the increased risk of congestive heart failure. Hyperphosphatemia, hypercalcemia, increased levels of calcium phophorus products (CaxP) and high levels of vit D sterols and high levels of PTH are effective in the pathogenesis of cardiovascular calcifications. However, in adult patients, 40% of patients with stage 3 CKD without these risk factors, there are evidences of calcifications. This suggests that other uremic factors beside Ca, P are also effective (25,26). Vascular calcifications are associated with increased mortality. Vascular and soft tissue calcifications are strong predictor of cadiovascular mortality in patients with advenced CKD. In a

Figure-4: Brown tumor and bone cysts in long bones Figure-5: Vascular calcification in ulnar, radial and digital arteries


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retrospective study, phosphate found to be more than 6.5 mg/dl, and CaxP level greater than 72 were detected to be contributing factors to high mortality (27). The mortality rate in children and adult CKD are higher than in normal population. Cardiovascular diseases cause death in oth children and adult patients. A 40% of deaths in CKD are from cardiovascular diseases and the risk of cardiovascular mortality is 10-70 times higher than the normal population. Normalization of the mineral metabolism is effective in slowing the progression of cardiovascular calcifications (5,6,23,24). In addition, left ventricular hypertrophy is a significant complication of advenced CKD, which is associated with myocardial fibrosis, poor perfusion and cell death. Vascular calcification in the pathophysiology increases the cardiac afterload as a consequence of increased arterial resistance (25). High PTH levels have a significant role in the development of left ventricular hypertrophy and reducing left ventricular ejection fraction. Reduction of PTH with parathyroidectomy or medical treatment improves the left ventricular ejection fraction significantly and restores myocardial hypertrophy (25). Visceral calcifications may occur in the lungs (causing restrictive lung disease), myocardium, mitral valve, kidney, skeletal muscles, breast, stomach and penis (22,24). Since vascular and valcular calcifications are irreversible, relatively early parathyroidectomy is recommended for the prevention of progression of ectopic calcification and cardiovascular diseases (26). Calciphylaxis is a rare and highly morbid condition that has continued to challenge the medical community since its early descriptions. Calciphylaxis clinically presents with severe painful skin lesions (livedo reticularis, reticulate purpura, violaceous plaques, or indurated nodules) that heal poorly and are frequently complicated by blistering and ulcerations with superimposed infections (Figure-6a). Ulcerated lesions commonly demonstrate black eschar (Figure-6b). Although skin manifestations characterize the clinical presentation, patients have been reported to have vascular

calcifications in skeletal muscle, brain, lungs, intestines, eyes, and mesentery. On this point, calciphylaxis can be considered as the continuing systemic process leading to arterial calcification in many vascular beds. Histologically, calciphylaxis is characterized by calcification, microthrombosis, and fibrointimal hyperplasia of small dermal and subcutaneous arteries and arterioles leading to ischemia and intense septal panniculitis. It is associated with significant morbidity and mortality. Mortality rates in affected patients may be up to 80%. A multi-disciplinary and multi-interventional approach by nephro logy , dermato logy , dermatopathology, wound or burn center, nutrition, and pain management departments is crucial (28). In patients with calciphylaxis who are treated with parathyroidectomy, wound healing is enhanced and median survival is prolonged (29).

Figure-6: a: Ulcerative calciphylaxis lesion in the dorsal aspect of the 3. finger, b: Necrotic black eschar in the 3. fingernail pulp



Renal osteodystrophy is a complex disease. Biochemical and imaging tests do not efficiently predict the underlying bone histology. Thus, although bone biopsy is invasive and difficult to perform in some patients, it is the gold standard for the diagnosis of renal osteodystrophy (30). The KDIGO guideline suggested that in patients with CKD stages 3-5, it is reasonable to perform a bone biopsy in various settings, including, but not limited to, unexplained fractures, persistent bone pain, unexplained hypercalcemia, possible aluminium toxicity, and before bisphosphonate therapy in patients with CKD-MBD (31).

Biochemical Laboratory Tests (Table-4)

The monitoring of serum levels of Ca, P, PTH, and alkaline phosphatase (ALP) at the beginning in adults with CKD stage 3 and in children with CKD stage 2 according to the KDIGO (Kidney Disease:Improving Global Outcomes) clinical practice guideline is recommended (31). The guideline recommends Ca and P tests every 1-3 months in stage 5 CKD, PTH every 3-6 months, and ALP every 12 months or more if needed (31).

Serum calcium level: It can be low, normal or high. Hypercalciuria occurs in advanced stage SHPT because of autonomy due to nodular hyperplasia. In the KDIGO guideline, Ca is recommended to be kept within the normal reference limits (31).

Serum phosphorus level: As the disease progresses in CKD, hyperphosphatemia generally occurs unless the positive phosphate balance is interfered. However, hyperphosphatemia does not become evident unless the glomerular filtration rate (GFR) drops below 30%. Hyperphosphatemia occurs in the stage 4 of the CKD. Compensatory

hyperparathyroidism till late-stage CKD tries to maintain normal P rates by increasing phosphate excretion from the kidneys in order to be able to maintain normal phosphate levels. The main causes of hyperphosphatemia are the decreased renal phosphate excretion in advanced CKD, persistence of compulsory P absorption from the intestines, and release of P as a consequence of bone resorption due to high PTH. It is recommended to keep P levels between normal limits such as Ca in KDIGO guideline.

Serum PTH level: High levels of PTH are associated with a decrease in 1.25-(OH)2 vit D3 biosynthesis, decreased expression of CaSRs on the parathyroid surface and hyperphosphatemia. It progressively increases with the progression of the disease. PTH increases up to 3-fold of the normal levels are accepted physiologically to compensate the low levels of 1.25-(OH)2 vit D3. As SHPT progresses, PTH increases and it is necessary to increase the dosage of the medical treatment. The only treatment option for the PTH levels that are resistant to medical treatment is surgery. In the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (NKF KDOQI)™ clinical practice guideline published in 2003, it was suggested that PTH levels in stage 5 CKD be maintained between 150-300 pg/mL (6). The 2009 KDIGO guideline, however, suggests that the reference values of PTH should be maintained between 2-9 times (31).

Vitamin D level: 1.25-(OH)2 vit D3 levels drop in the early phase of CKD without any change in serum Ca and P concentrations and without any increase in serum PTH levels. With the reduction of functional renal parenchyma, the reduction of 1-alpha hydroxylase activity results in a decrease in the production of 1.25-(OH)2 vit D3. In the late phase, phosphate retention and hyperphophatemia directly suppress 1-alpha hydroxylase activity. It is suggested in KDIGO guideline that 25-OH vit D deficiency or insuffiency should be corrected by treatment according to the recommendation in the general population (31).

Table-4: Laboratory findings of secondary hyperparathyroidism

• Ca: Low, Normal, High• P: Normal, High• PTH: Normal, High• Vitamin D metabolites: Low• Alkaline phosphatase: High


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Alkaline phosphatase: Circulating PTH or bone-specif ic ALP levels correlate with some histomorphometric measurements in bone biopsy specimens (30). PTH alone is not a good predictor of BMD with high and low turnover, except for respectively very high or very low values. ALP can provide additional information on bone turnover (31). ALP is high in high turnover MBD and low in low turnover MBD.

Differential Diagnosis of Hypercalcemia in Chronic Kidney Disease (Table-5)

Hypercalcemia can occur for a variety of reasons in patients with CKD. In patients with CKD, it is especially important to distinguish osteitis fibrosa cystica which is characterized by high turnover bone disease that is a classical sign of severe SHPT, from adynamic bone disease which is characterized by especially low turnover bone disease. PTH is high, Ca is normal or high and ALP level is high in osteitis fibrosa cystica. In adynamic bone disease, PTH level is low, Ca level is high, and ALP level is low. Excessive Ca or vit D treatment may be detected from the patient’s treatment. Differential diagnosis of hypercalcemia due to osteitis fibrosa cystica should also be made in terms of immobilization, malignity and granulomatous diseases.

MEDICAL MANAGEMENT

Curative management in patients with CKD-related SHPT requires renal transplantation, which results in normalization or near normalizasion of serum Ca, P, and PTH levels in up to 95% of patients, when successful (16). Although treatment of patients with SHPT is predominantly medical, curative

medical therapy remains to be developed. Given that the underlying cause for SHPT is overstimulation of the parathyroid glands, medical treatment is focused on reducing that stimulation (1). Because of the independence of Ca, P, and vit D metabolism, multiple pathways can be targeted by medical therapies centered around three main principles: Controlling hyperphosphatemia (dietary phosphate restriction, phosphate binders), vit D/analog replacement, calcimimetic agents and Ca replacement (16). Agents used in medical treatment are summarized in Table-6. Phosphate control should begin with restriction of daily dietary phosphate intake to less than 900 mg. Phosphate-binding agents should be added when dietary restriction and, if applicable, dialysis fail to consistently produce serum P levels below 5.5 mg/dL (16,17). Vit D deficiency is highly prevalent in patients with end-stage CKD. If vit D deficiency or insufficiency are present, vit D analogs (e.g. calcitriol) should be initiated. While effective at decreasing serum PTH, vit D analogs may also cause increases in serum Ca and P (17). Calcimimetics have transformed the medical management of SHPT. They increase the sensitivity of the CaSR in the parathyroid gland, leading to a reduction in circulating PTH concentrations within 1-2 h after dosing. Currently cinacalcet (mimpara) is the only available oral calcimimetic (16,17). Routine

Table-5: Differential diagnosis of hypercalcemia due to chronic renal failure

• Severe SHPT• Adynamic bone disease• Excessive Ca treatment• Excessive vitamin D treatment• İmmobilization• Malignity• Granulomatous diseases

Table-6: The commoly used pharmacological agents in patients with CKD for controlling SHPT (VDRA: vitamin D receptor activator)

• Phosphate binders – Calcium carbonate, calcium acetate – Sevelamer hydrochloride and sevelamer carbonate – Lanthanum carbonate• Aktive vit D sterols, vit D receptor activators (VDRA) – Calcitriol (1.25 (OH)2 vitD3) (non-selective VDRA) – 22-oxacalcitriol – Cholecalciferol (25(OH) vitD3) – Ergocalciferol (25(OH) vitD2) – Alpha-calcidol (1(OH) vitD3) (non-selective VDRA) – Doxecalsiferol (1(OH) vitD2) (non-selective VDRA) – Paricalcitol (19-nor-1.25 (OH)2 vitD2) (selective synthetic VDRA)• Calcimimetics – Cinacalcet HCI • Reduces parathormone secretion • Regulates calcium phosphorus balance



cinacalcet therapy reduced the need for parathyroidectomy in adults treated with dialysis and elevated PTH levels but does not improve all-cause or cardiovascular mortality. Cinacalcet increases r isks of nausea, vomiting and hypocalcaemia (3). Phophate-binders, vit D analogs, calcium, calcimimetics can be combined in the patient-specific medical treatment. The assessment of treatment and dose adjustment are performed with serum Ca, P, PTH measurements. Serum total Ca, P, PTH levels are measured weekly until the treatment regimen stabilizes, then every 1-3 months. As vitamin D levels change slowly, it is evaluated every 3-6 months (16).

SURGICAL INDICATIONS

Although novel medical treatments for patients with SHPT have been introduced, surgical intervent ion is s t i l l necessary at t imes. Approximately 1% to 2% of patients with SHPT require parathyroidectomy each year (14). Contraversy remains concerning the indications for surgical parathyroidectpmy (PTX). The indications for PTX in SHPT are summarized in Table-7. KDQOI guideline recommends surgery in the p resence o f hyperca lcemia and /o r hyperphosphatemia with PTH values above 800 despite 6 months of medical treatment (5). However

PTX may be more suitable than cinacalcet treatment when the condition is intractable to cinacalcet treatment, or when cinacalcet cannot be managed because of other adverse medical events or poor patient compliance, and when sufficient reduction in PTH cannot be obtained with cinacalcet (26,33). Although very rare, cinacalcet may be the first choice for patients in whom surgical HPT management appears challenging, e.g., in patients at risk for general anesthesia when mediastinal approach becomes necessary; reoperative surgery when parathyroid glands remain completely unlocalized; or in patients with a previous percutaneous ethanol injection (14,17,26,33). Calciflexia is accepted as a strong indicator for parathyroidectomy, and 4% of patients undergoing PTX are in this group (14). Parathyroid gland diameter and presence of nodules are suggested by some investigators as an indication for surgery. Nodular hyperplasia is most likely to develop in parathyroid glands whose largest diameter measured with USG is greater than 1 cm or volume exceeding 500 mm3 (26). Surgery may be indicated in cases with long life expectancy, uncontrollable with Cinacalcet, and with pruritis, severe bone pain, muscle weakness, advanced osteoporosis/osteopenia, pathological bone fracture, advanced mental status changes, depression, arythropoietin-resistant anemia, diastolic cardiomyopathy (14,17,26,33).

Table-7: Indication for parathyroidectomy in patients with SHPT

• High PTH level with medical treatment of SHPT, with a duration of >6 months; with values of >500-800 pg/ml); with;

– Hypercalcemia (>10-10.2 mg/dl) and/or– Hyperphosphatemia (>6-6.5 mg/dl)

• Volume of the parathyroid gland with USG > 500 mm3 or diameter > 1 cm• Patients who are expected to have a long-term survival with severe symptomatic SHPT

– Advanced osteopaenia/osteoporosis– Intractable bone pain – Patologic bone fracture– Ectopic soft tissue calcification– Severe vascular calcifications– Mental status change– Pruritis– Calciphylaxis– Erythropoietin resistant anemia– Diastolic cardiomyopathy


M. Uludag

PRE-OPERATIVE IMAGING

Although USG and parathyroid sestamibi scintigraphy are currently routinely used in primary hyperparathyroidism in preoperative imaging, preoperative imaging is not routinely performed in the initial surgery in SHPT. Theoretically, the idea that preoperative imaging may help in locating the pathological orthotopic or ectopic gland is valid for single gland disease. However, SHPT is generally characterized by multiglandular hyperplasia. The sensitivities of preoperative imaging modalities such as 99mTc-sestamibi and USG are poor in multigland disease and SHPT (14,17,34). Ectopic mediastinal glands were identified in only 38% of patients with secondary and tertiary HPT, which were found to be bearing mediastinal parathyroids at surgery (14,34). Another logical basis for not performing preoperative imaging is the possibility of changing the shape of the surgery using preoperative imaging methods is very low, since bilateral exploration is the standard approach in patients with SHPT (14). In contrast to primary surgrey, imaging studies to localize the enlarged parathyroid gland(s) are indicated in patients with persistent and recurrent SHPT. Imaging prior to primary surgery may also have contribution in some aspects (34). If an ectopic or supernumerary gland is detected preoperatively, removal of this gland in addition to bilateral exploration may reduce the likelihood of persistent and recurrent disease. It may help to choose the remnant to be le f tor the gland that wi l l be used for autotransplantation. Since the glands with intense involvement in scintigraphy may be mostly autonomous glands, when these glands are primarily removed, glands that do not retain activity or retain low activity can be used for remnant tissue. In addition, in regions such as our country, where nodular goiter is endemic, USG provides preoperative detection of a nodular thyroid pathology that may require examination and treatment. This contributes to the planning of both thyroid and parathyroid surgery at the same session.

SURGICAL MANAGEMENT

In the literature, four surgical procedures were reported for the primary surgical management of SHPT:1. Subtotal parathyroidectomy (Subtotal PTX) with

bilateral cervical thymectomy (BCT) 2. Total parathyroidectomy with autotransplantation

(AT) of parathyroid tissue and bilateral cervical thymectomy (TPTX+AT+BCT)

3. T o t a l p a r a t h y r o i d e c t o m y w i t h o u t autotransplantation of parathyroid tissue and without thymectomy (TPTX)

4. T o t a l p a r a t h y r o i d e c t o m y w i t h o u t autotransplantation of parathyroid tissue and with bilateral cervical thymectomy (TPTX+BCT)

1. Subtotal parathyroidectomy: Subtotal PTX is the resection of approximately 3.5 parathyroid glands, leaving between 40-80 mg of the most normal appearing parathyroid gland well-vascularized in situ. The remnant parathyroid tissue is marked with a metallic clip or a non-absorbable suture.

2. Total parathyroidectomy with autotransplantation: TPTX+AT involves identification and resection of all four parathyroid glands and any supernumerary parathyroid glands. The most normal-appearing gland for autotransplantation should be minced into 10-20 1 mm3 pieces for re-implantation. The brachioradial muscle of the non-dominant forearm, the sternocleidomastoid muscle, the subcutaneous fat of the forearm or abdomen are all potential sites for re-implantation. In all case, the site of reimplantation should be marked with a metallic clip or non-absorbable sutures so that it can be found in case of necessary re-intervention (17,33,34). Reimplantation into the forearm may prevent the need for surgical re-exploration of the neck in the event of recurrent HPT due to graft hyperplasia. Reoperation in these patients can be done under local anesthesia (14,33).

3. T o t a l p a r a t h y r o i d e c t o m y w i t h o u t autotransplantation: During this surgical approach, at least four parathyroid glands should be resected. Unilateral timectomy will be only performed if less than two gland are identified on



the respective side or if palpation revealed a suspicious nodule within the thymus.

4. T o t a l p a r a t h y r o i d e c t o m y w i t h o u t autotransplantation of parathyroid tissue and bilateral cervical thymectomy: This technique is intended to remove all parathyroid tissue in the body. With 4 parathyroid glands, the thymus, which includes the ectopic parathryoid glands and parathyroid cell rests the most, is also removed. The main drawbacks against this surgery are hypocalcemia treatment after total parathyroidectomy and the difficulty in medical follow-up. This surgery type was evaluated only in a small series of 23-patients in the literature; even though adynamic bone disease and treatment difficulty were not encountered, it is inadequate to make a clear deduction from these results (35).

Thymectomy in Secondary Hyperparathyroidism

Despite their distinct primary functions, the parathyroid and thymus organs have a close relationship during organogenesis, initially developing from two shared parathyroid/thymus primordia originating from the bilateral third pharyngeal pouches. In humans, ectopic parathyroid tissues have been found most commonly in the thymus (34). The frequency of intrathymic parathyroid glands or parathyroid cell rests in patients undergoing PTH for SHPT varies significantly between 14.8% and 45.3% (36). Intrathymic parathyroid glands were detected in 27 (28.4%) of 95 patients who underwent secondary parathyroidectomy due to recurrent hyperparathryoidism (37). In another study where surgery was performed for persistent and recurrent HPT due to missed parathyroid glands, 48% of ectopic missed parathyroid glands were detected in ectopic localization. The rate of ectopic parathyroid glands was found to be 13% in patients who underwent thymectomy in the first operation and 50.8% in patients without thymectomy (38). For this reason, routine BCT is recommended with subtotal PTX and RPTX+AT by many investigators (32,36-38). Because of the low frequency of supernumerary intrathymic parathyroid glands and a

suspected low proliferation stimulus, the relevance of BCT after resection of four glands in predialysis patients and those after successful kidney transplantation must be questioned (36). There is presently no sufficient data to give a definitive comment about the value of routine BCT during TPTX without autotransplantation (33).

Which Surgery Should Be Preferred in Primary Surgery in Secondary Hyperparathyroidism?

The surgical strategy in SHPT should be focused on an appropriate balance between PTX, prevention of persistent/recurrent disease and avoidance of postoperative permanent hypoparathyroidism. These objectives cannot be guaranteed with any of the procedures at hand. In the literature, the rates of subtotal PTX, TPTX + AT, TPTX, and TPTX+BCT were 19.8%, 68.1%, 10.3% and 1.6%, respectively (33). Approximately 90% of the operations performed are subtotal PTX and TPTX + AT. In the literature, subtotal PTX studies which were randomized controlled or involving more than 50 patients were reported to have a mean recurrence rate of 8.2% (0-20) and a hypoparathyroidism rate of 2% (0-10.9%) (33). In TPTX + AT studies, recurrence rate is reported as a mean value of 4.8% (0-12) and hypoparathyroidism rate as 2.2% (0-15) (33). The only prospective randomized study comparing the result of 40 patients with either subtotal PTX or TPTX+AT showed significantly decreased rates of recurrence, significantly more often normalization of serum calcium and ALP and, significantly improved clinical signs such as pruritis and muscle weakness after TPTX+AT, compared to subtotal PTX (39). However, this prospective randomized study was underpowered to lead to standardization of this surgical procedure. In comparative studies which include this study and the other retrospective studies in the literature, that compare these 2 methods, the mean recurrence and hypoparathyroidism rates were detected as 6% (3.7-20), 2.4% (0-10.9) for subtotal PTX, and and 5.2% (0-6), and 1.6% (0-6) for TPTX+AT, respectively, being similar to each other. The main cause of recurrence for both subtotal PTX and TPTX+AT is inadequate initial surgery (40).


M. Uludag

In the literature, recurrent/persistent SHPT rates following TPTX surgery in retrospective case series involving 11-150 patients were reported to be 0-4%, and hypoparathyroidism rates between 0-7%. Patients after TPTX without thymectomy did not develop hypoparathyroidism and especially adynamic bone disease as initially expected. Even in case of resection of all four parathyroid glands (TPTX), residual microscopic parathyroid rests or supernumerary glands located in the thymus may prevent the patients to develop hypoparathyroidism (33). There is only one retrospective study on 606 patients with SHPT comparing subtotal PTX, TPTX+AT and TPTX (41). It is reported that all three surgical procedures for PTX are feasible and safe with an effective decrease in Ca and PTH levels. On the other hand, the authors critically discuss subtotal PTX and remark that recurrent disease requires a neck re-exploration with a higher rate of morbidity (41). TPTX without AT may result in adynamic bone disease. The first prospective randomized controlled multicenter pilot trial (TOPAR-PILOT) was performed between 2007-2013 to compare TPTX without AT and TPTX+AT settings with long-term follow-up. The data on both operative methods published at the time of study plan led to a calculated number of patients of more than 4000 in each management arm to be able to perform a confirmatory trial to prove superiority of TPTX over TPTX+AT with regard to a lower recurrence rate (42). Because such a trial was unrealistic given the rarity of the disease, it was decided to run a non-confirmatory multicenter randomized controlled pilot trial on 100 patients to establish a hypothesis that could be tested thereafter. In the prospective study, 52 patients were randomized to TPTX, and 48 patients to TPTX+AT group (43). Persistence and recurrence developed in 1, 2 and 0, 4 patients, respectively. The difference was significant (p=0.02) between 36th month PTH levels, as being 31.7+43.6 ng/L and 98.2+156.8 ng/L, respectively (p=0.02). The recurrence rate in this study was significantly higher after TPTX+AT (8.3%) than after TPTX (0%) (p=0.03). However, authors reported that all 4 TPTX+AT patients with recurrent SHPT were operated in the same center and the significance of the observed difference is therefore highly

questionable, as potential bias has to be assumed. In all patients, surgery was performed according to the protocol with 4 parathyroid glands resected together with the thymic tongues. Till date, no localization studies were performed to localize the origin of recurrent SHPT, but the parathyroid autografts have to be assumed the most likely source of PTH production. None of the patients with recurrent SHPT developed hypercalcemia or underwent reoperation for the mild recurrence during the 36 months follow-up. They suggested that reasons for this outcome could have been, for example, an inadequate selection of the tissue selected for AT and/or an inadequate number and/or size of transplanted tissue fragments. In conclucion, they argued that despite the fact that this trial cannot definitely answer the question whether TPTX is superior or equal to TPTX+AT, it can be concluded that TPTX+AT and TPTX seem to be effective for the treatment of otherwise unconrollable SHPT and that TPTX is a feasible alternative therapeutic option (43). There is not still enough evidence-based information available at this time to declare one approach superior to another. The surgical approach performed is often due to surgeon’s preference (1,14). Resection of less than 3.5 parathyroid glands in patients with SHPT may not be considered an adequate option due to the high risk of persistence/recurrence (44,45). Based on numerous studies on surgical management of SHPT, it should be stated that both subtotal PTX and TPTX+AT and standard servical thymectomy represent standard procedures that ensure a postoperative success with an acceptable and satisfactory percentage of permanent hypoparathyroidisim (5,14,33). Based on the available data, TPTX with or without AT can be considered as safe standard techniques for patients on permanent dialysis and otherwise uncontrollable SHPT (1,33). With lack of convincing data to support one operation over the other, the authors recommend that the individual surgeon make the choice that he thinks will succeed, and the operation must be done with meticulous technique and minimal complications (1). Subtotal PTX may be the preferable approach in predialytic patients (moderate patients), and in patients with SHPT awaiting a kidney



transplantation in the future. Because it was shown that subtotal PTX deteriorates kidney function less than TPTX+AT due to the postoperatively less pronounced transient hypoparathyroidism, which may provoke reduced graft perfusion, as one possible cause of kidney graft deterioration associated with PTX. TPTX may be preferable for patients on permanent dialysis (stage 5 CKD) and otherwise uncontrollable SHPT (46,47). Both the KDOQI and Japanase Society for Dialysis Therapy guidelines recommend that TPTX without AT should be contraindicated in patients with SHPT who are on a waiting list for kidney transplantation, because control of the serum Ca level may be difficult following kidney transplantation (5,48). Therefore, TPTX with and without AT may be preferable surgical procedures in patients with SHPT who are not candidate for kidney transplantation (1,33,45).

Persistent or Recurrent SHPT

Persistent SHPT generally results from inadequate initial resection or a missed fifth or ectopic gland and reoperation may be required (14). Recurrence after initial surgery for SHPT is not uncommon. Regrowth of the residual parathyroid tissue after subtotal TPX or TPTX+AT may occur depending on the time interval and ongoing stimulation of the remnant, especially when kidney transplantation is not feasible. In up to 15.5% of patients, supernumerary glands may be the cause for recurrent or persistence disease (37). Morbidity following cervical re-exploration is still high due to scar formation associated with initial surgery. The cause of persistence or recurrence must be defined, since it is important for the reoperative surgical strategy. It is obligatory to review all operative notes and pathology reports from the previous operation(s) as well as previous localization studies (33). Once the diagnosis of recurrent and persistent SHPT is confirmed, one must decide whether reoperation is required. In contrast to initial surgery, imaging studies to localize the enlarged parathyroid gland(s) are mandatory. These imaging modalities should at least include neck USG and sestamibi single-photon emission CT scintigraphy. MRI of the neck and mediastinum,

methionine positron emission tomography (PET-CT) or selective venous sampling, depending on results of previous localization studies may be considered. There is a general agreement that reoperative surgery is indicated, if a targeted approach to either the neck or autograft site is possible as it holds the lowest complication rate (33,37,49).

Complications

The most common complication of PTX is protracted hypocalcemia. This is precipitated by accelerated bone remineralization (hungry bone syndrome) and delayed forearm graft or cervical remnant function. Temporary hypocalcemia often requires agressive therapy with intravenous and oral Ca, injectable and oral vitD/analog supplementation, and high Ca dialysate. However, severe and permanent hypocalcemia requiring prolonged admission for longer than 1 week or readmission for intravenous Ca is also seen, but much less fequently (<7%). Supplementation of elemental Mg should be started if serum Mg concentration declines below 1.5 ng/dl. Prophylactic Ca and calcitriol treatment can be started before surgery (14,17,33). Permanent recurrent laryngeal nerve paralysis rarely occur (<1%), particularly in experienced hands. Other complications such as wound infection, hematomas, dehiscence, have been described, but are seldom seen (14).

Benefits of the Parathyroidectomy

Information from the United States Renal Data System for Medicare and Medicaid patients on dialysis showed that PTX was associated with higher short-term (3.1% PTX vs 1.2% control, 30-day mortality), and lower long-term (53 vs 47 months) mortality rates among U.S. patients receiving chronic dialysis (50). Komaba et al. (51) analyzed the effect of PTX on survival among Japanese hemodialysis patients with severe, uncontrolled SHPT. They found that in the propensity score matching analysis, patients who had undergone PTX had a 34% and 41% lower risk for all-cause and cardiovascular mortality, respectively, compared to the matched controls.


M. Uludag

PTX for patients with SHPT results in dramatically reduced PTH levels, improved control of serum phosphorus and calcium levels, amelioration of SHPT-related symptoms, histological improvement in high-turnover bone disease, and increased bone mineral density. Furthermore, observational studies suggest the potential of PTX to reduce the risk of bone fracture (52). It is well-known that calciphylaxis and tumoral calcinosis are generally markedly improved by PTX. Unfortunately, vascular and valvular calcifications are usually not affected, even by successful PTX. Diastolic cardiomyopathy is

markedly improved after PTX (26). Uremic pruritis is often relieved by PTX (14). PTX may also improve the weakness, muscle strength, nutritional status, and humoral and cell-mediated immunity and blood pressure in patients with SHPT (17,26). Improved neuropsychiatric symptoms, and quality of life with reduced cardiovascular events also are benefit of PTX (14).

Acknowledgement: I would like to thank Dr. Rafi Armağan, who provided the radiographs of the patients who had parathyroid surgeries in our clinic.

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