6 курс / Нефрология / Острое_повреждение_почек_после_паратиреоидэктомии_по_поводу_первичного
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PHPT include delayed bile evacuation caused by PTH relaxing effect on smooth muscle cells, decreased bile ionized calcium level due to hypercalcemia and sphincter of Oddi dysfunction [120]. In contrast to pancreatitis, GD in PHPT is more common in women.
Cardiovascular system.
Primary hyperparathyroidism is associated with an increased risk of arterial hypertension, which occurs in 40–65% of cases [145]. Among the possible mechanisms for arterial hypertension (AH) in PHPT patients are renin-angiotensin-aldosterone system activation [31, 183], inadequate vessels total peripheral resistance due to impaired vasodilation capacity [98] and/or increased vasoconstriction in response to pressor hormones secretion [ 128, 150]. According large national registry analysis, PHPT was indicated as an independent predictor of hypertension risk, being diagnosed in 0.1% of 37922 hospitalizations (odds ratio [OR] = 1.3; p <0.001) [91].
There are evidences of arterial hypertension course improvement after a PTx [67, 73], however the only randomized controlled trial conducted to date did not confirm this conception [55].
Potential cardiovascular complications in PHPT include left ventricular hypertrophy [115] and diastolic dysfunction [111], as well as heart valves calcification [88, 187]. Hypercalcemia in PHPT causes a shortening of the QT interval, leading to arrhythmias development - both ventricular and supraventricular extrasystoles [144, 146]. The increased risk of cardiovascular mortality with PHPT has been demonstrated in studies with symptomatic PHPT patients, however this was absent in case of asymptomatic disease [37].
Neurocognitive disorders.
The nervous system involvement in PHPT was first described in the XX century thirties, simultaneously with the description of the disease itself. Patients with PHPT demonstrate muscle weakness, cognitive impairment, anxiety, depression, and quality of life decrease [110, 136, 194]. These could possibly be explained by an important physiological role of calcium as a neurotransmitter, as well as the PTH receptors in the
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brain tissue and its direct effect on the central nervous system [86]. Based on the data available at that time, the 2014 Consensus on the Management of Asymptomatic PHPT did not recommend considering neurocognitive disorders as a PTx indication. However, a series of prospective cohort studies performed later using validated questionnaires and computerized unit tests showed significant improvement in the symptoms after a surgery [160].
1.3. PHPT classification and main treatment approaches.
Depending on the clinical symptoms severity, manifest, mild (asymptomatic) and normocalcemic PHPT forms are considered. Expert consensus proposed this classification in 2014 under the 4th international workshop on the treatment of asymptomatic PHPT [165].
The normocalcemic form of PHPT (nPHPT) is the disease phenotype that implies no increase in total and ionized calcium levels, however PTH level is persistently increased in patients with no possible causes for secondary PTH increase in the anamnesis. This form was first identified in 2009 [24]. To confirm the diagnosis of nPHPT, at least two measurements of total and/or ionized calcium and PTH levels are required in the interval of 3-6 months. Possible causes of a secondary PHT increase may be vitamin D deficiency (of less than 20 ng/mL), CKD stage 3 or worse, specific medications (thiazide diuretics, loop diuretics, lithium agents, bisphosphonates, denosumab), as well as malabsorption with impaired calcium absorption.
The mild (asymptomatic) form of PHPT is characterized by the absence of the classic clinical PHPT manifestations. Serum calcium and PTH level increased are accidentally found during a laboratory examination that is the main way to detect the disease form. The diagnosis of mild PHPT takes place if total blood calcium level does not exceed the upper limit of normal adopted in a particular laboratory for 1 mg/dL (0.25 mmol/L). Dual-energy X-ray osteodensitometry may detect moderate osteopenia, defined as a decrease in BMD according to the T-score by no more than 2.5 standard deviations (SD) from the BMD normal established for young people in any skeleton part measured (lumbar vertebrae, proximal femur, middle third of the radius).
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Manifest form. Characterized by a bright clinical picture with the involvement in the pathological process of target PHPT organs. Depending on the damage of particular organs and tissues, bone, visceral and mixed forms are distinguished:
●bone form - hyperparathyroid osteodystrophy, osteoporosis, lowenergetic fractures anamnesis;
●visceral form – renal injury, gastrointestinal tract and cardiovascular organs damage;
●mixed form – a combination of bone and visceral forms [1].
Surgical treatment is the main and most effective method of PHPT treatment [24]. The effectiveness of surgical treatment performed by an experienced surgeon reaches 9598% with a frequency of postoperative complications of 1-2% [100]. The results of successful PTx include BMD improvement, fractures risk reduce, stone formation incidence reduce and neurocognitive disorders reverse [118].
Among the variety of surgical approaches to PHPT treatment, the most popular at present is minimally invasive (selective) PTx. To use this method, high-quality preoperative topical diagnosis and the mandatory use of intraoperative PTH monitoring are necessary. The use of selective PTx can minimize the traumatic effect on the tissues, as well as significantly reduce the intervention duration, since skin incision of the minimum size is performed by the surgeon directly in the area of the adenoma, and only the affected PTG is removed, without revision and injuring the other glands in case of the surgery effectiveness is confirmed. The effectiveness of PTx is defined as a PTH level decrease by more than 50% 10-15 minutes after the complete removal of the hyperfunctioning parathyroid tissue (adenoma, hyperplastic glands) – i.e., the so-called Miami criterion (protocol) [87]. It is worth noting, that the recommendations emphasize the importance of the surgery for PHPT to be performed exclusively by specialist who are highly qualified in parathyroid surgery.
According to the National Clinical Guidelines for the Diagnosis and Treatment of PHPT, the absolute indications for surgical PHPT treatment are:
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1)total serum calcium concentration exceeding the normal established in the laboratory by 0.25 mmol/L (1 mg/dL);
2)GFR decrease of less than 60 mL/min/1.73 m2;
3)visceral PHPT manifestations;
4)daily calcium excretion of more than 400 mg (10 mmol);
5)BMD decrease at any of the three points (radius, femur, spine) of less than -2.5 SD according to the T-score;
6)low-energy fractures anamnesis and/or fractures of the vertebral bodies, identified by X-ray, multispiral CT or magnetic resonance imaging;
7)age under 50 years.
Minor discrepancies between national and international clinical guidelines relate to items 3 and 4. Thus, in the International Consensus for the Treatment of PHPT-2014 recommendations, only renal manifestations of the disease are considered as an indication for surgical treatment – i.e., nephrolithiasis and nephrocalcinosis, confirmed by ultrasound, radiography or CT. Other “non-classical” organs damages are not absolute indications for PTx. Calciuria of more than 400 mg/day is considered an indication for surgical intervention only in combination with other risk factors for stone formation based on the results of biochemical urinalysis [23]. However, experts agree that highly effective surgical treatment may be an option even when it is not indicated by the existing criteria. Surgical treatment is also evidently feasible in terms of pharmacoeconomics compared to the observation and conservative treatment of patients with PHPT [210].
Conservative treatment is recommended for patients with a mild PHPT form in the absence of surgical treatment indications. In this case, the following parameters are monitored:
•blood calcium levels - 2-4 times a year;
•blood creatinine level, GFR calculation - once in 6 months;
•PTH level - once in 6 months;
•daily urine calcium excretion – once in 6 months;
•kidneys ultrasound - once a year, and CT if necessary;
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• BMD measurement at three points once a year; spine lateral radiography in case of suspected vertebral bodies fractures (decrease in growth, back pain);
• fibrogastroduodenoscopy – once a year [1].
In nPHPT, blood calcium and PTH levels should be controlled annually and densitometry should be performed once in 1-2 years. If the disease progresses to the hypercalciemic form, the above-described algorithm of control should be adjusted respectively. The decision on whether the patients with mild PHPT form and nPHPT are indicated for surgical treatment is based on their individual dynamics of laboratory and instrumental data. If BMD is progressively decreasing, GFR is below than 60 mL/min/1.73 m2, nephrolithiasis and pathological fractures occur, laboratory parameters have negative dynamics, the surgical treatment is recommended [23].
Patients with manifest form of PHPT can be treated conservatively if refuse to undergo the surgery or there are contraindications to surgical treatment (severe concomitant pathology).
All patients are advised to drink enough water and avoid calcium restriction diets, as it can deteriorate PHPT course. Calcium small doses are not recommended for patients with PHPT and osteoporosis, although do not aggravate hypercalcemia and hypercalciuria in case of calcium deficiency diet [90].
The 2014 International Recommendations suggest to prescribe vitamin D in small doses to restore its level to 21-30 ng/mL, based on evidence of PTH level reduce [112]. In a recent randomized placebo-controlled study of cholecalciferol at a dose of 2800 U a day, it was shown that an increase in serum vitamin D levels from 20 to 37.8 ng/mL led to a decrease in PTH levels, increased BMD of the lumbar spine with no PTH or serum calcium levels increased [151].
If conservative management is necessary, antiresorptive agents and/or calcimimetics are used to reduce bone loss and correct hypercalcemia.
Biphosphonates inhibit bone resorption, reducing the activity of osteoclasts, increase BMD, contribute to the formation of bone tissue with normal architectonics. Biphosphonates can be recommended for conservative treatment of patients with PHPT and osteoporosis, low-energy fractures anamnesis or fractures high risk. However, none
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of the drugs in this group is approved specifically for the treatment of PHPT. The largest evidence base exists for alendronic acid. In several randomized controlled trials, alendronic acid significantly increased BMD of lumbar spine and femur without blood calcium and PTH levels increase [94, 152], however to date, there is no data on fractures risk reduction with its use. For other drugs in this group - zolendronic acid, pamidronic acid, ibandronic acid - there is no data on BMD dynamics in patients with PHPT [134]. The use of biphosphonates is contraindicated with GFR of less than 30 mL/min/1.73 m2.
Denosumab is a human monoclonal antibody, binding to the receptor activator of the nuclear factor xB ligand (RANKL) on the surface of osteoclasts and their precursors, which inhibits the formation, activation and life span of osteoclasts. To date, data from the only retrospective study of the denosumab use in elderly women with PHPT have been published, which shows BMD increase in the femur [59]. In general, due to the data on denosumab use in elderly PHPT women is lacking, the product is not recommended for PHPT treatment at the moment.
Cinacalcet is a calcimimetic agent with the mechanism of action allowing to increase the CaSR sensitivity to extracellular calcium. Cinacalcet effectively reduces calcium levels in patients with PHPT [50], and was approved by the European Medicines Agency (EMA) in 2008 and the Food and Drug Administration (FDA) in 2011 for the treatment of patients who are contraindicated for surgical treatment, due to severe comorbidity. However, cinacalcet therapy does not have a positive effect on BMD and urine calcium excretion, and data on its effect on nephrolithiasis risk is not yet available. Importantly, the side effects (nausea, vomiting, convulsions, headache) incidence of cinacalcet use is very high, and often treatment with this drug does not improve, but even worsens the subjective patient condition [130].
Summarizing the above, there is currently no equivalent PHPT treatment of as the surgery, since none of the existing pharmacological agents or their combinations can achieve the same effect of laboratory parameters normalization and BMD increasing as compared to surgical treatment.
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1.4. PHPT surgical treatment postoperative complications.
Surgical treatment of PHPT is effective in more than 95% of cases if performed by experienced surgeons [93], while the incidence of complications in the early postoperative period does not exceed 2% [96].
Postoperative mortality in surgical treatment of PHPT is extremely low (0.2%). Postsurgical complications include early ones (bleeding, postoperative wound suppuration, recurrent laryngeal nerve paresis) and late ones (disease persistence, recurrence, parathyromatosis).
Surgical area infections incidence in the early postoperative period according to various data ranges from 0.1 to 0.8% [54, 96]. Bleeding occurs in 1.5% of cases, recurrent laryngeal nerve paresis - in 0.5% of cases in surgical treatment of PHPT [129].
Persistence of PHPT is defined as hypercalcemia occurring within 6 months after the surgery, the incidence reaches 2.2%. The rate of PHPT recurrence (i.e., hypercalcemia occurring after 6 months or more after PTx) is 0.9%. Persistent disease occurs most likely after a selective PTx, while the recurrence rates after minimally invasive PTx and bilateral neck revision are comparable [129]. It should be noted the complication statistics described above are relevant for specialized endocrine surgery centers.
Parathyromatosis is an extremely rare surgical complication of PTx – i.e., hyperfunctioning parathyroid islets formation in the neck and upper mediastinum due to their traumatization during surgery.
Transient or persistent hypocalcemia is the main therapeutic complication of PTx for PHPT. Usually, blood calcium level reaches a minimum on day 2-3 postoperatively, does not last more than 4 days, and does not depend on the PTG size or their histological structure (adenoma/hyperplasia). Hypocalcemia, which persists for more than 4 days, can be caused by intentional or accidental removal of all PTG, devascularization or trauma of remaining PTG, prolonged suppression of normal PTG by parathyroid adenoma, as well as "hungry bone syndrome" [198]. The hungry bone syndrome is preceded by a severe bone form of PHPT with significant decrease in BMD, hyperparathyroid osteodystrophy and/or "brown tumors" development. Severe (hypocalcemia (total blood calcium level of less than 2.1 mmol/L) occurs due to rapid PTH level decrease and elimination of its
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resorptive effect on the bones, as well as sharp calcium intake increase with increased bone formation.
Data on hungry bone syndrome incidence is extremely contradictory: from 4% to 87% of all PHPT patients according to the results provided in various publications [198].
Clinical manifestations of hypocalcemia include paresthesia, muscle seizures up to tetany, laryngospasm, positive Khvostek and Trusso symptoms. Generalized seizures can lead to pathological fractures [45]. Hypocalcemia symptoms are generally observed with serum calcium level decrease of less than 1.9 mmol/L, however can also occur at higher levels in case of high decrease rate.
The hungry bone syndrome risk factors include old age, high preoperative blood calcium, PTH, alkaline phosphatase and osteocalcin levels, blood albumin and magnesium decreased levels [169, 198]. In order to prevent this syndrome, several researchers have attempted preoperative use of biphosphonates with a positive result, however all the studies were either retrospective observations with a small sample size, or isolated clinical cases [75,104].
Severe hypocalcemia treatment consists of intravenous and oral calcium agents in a total dose of up to 12 g/day and active vitamin D derivatives (2-4 μg/day) administration. Calcium gluconate is preferable for intravenous infusion, and a central venous catheter installation is recommended as venous access.
The data on incidence of the other non-specific PHPT therapeutic complications (acute myocardial infarction, acute cerebral circulation disorders) in the early post-PTx period is lacking. Their risk after surgical treatment of PHPT seems to be comparable with that after other non-cardiac surgeries [96].
1.5. Acute kidney injury in postoperative period.
Acute kidney injury (AKI) is defined as an acute renal function decrease, which is caused by both specific kidney diseases (acute glomerular and vascular kidney damage, acute interstitial nephritis) and nonspecific conditions (ischemia, toxic damage), as well as extrarenal disorders. AKI is a global problem of both outpatient and inpatient stages,
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and is widespread in therapeutic, surgical and oncological hospitals, as well as in resuscitation and intensive care units.
The first clinical description of acute renal failure (ARF, called that time "renal ishuria") was made by William Heberden in 1802. Acute Bright's disease was described in the "Manual of Medicine" by William Osler (1909) as pregnancy, injury and burns complication or toxic substances poisoning result. The term "acute renal failure" was first introduced by Homer Smith in his manual "Kidneys: Structure and Function in Normal and Pathology" (1951) [58]. However, there was no exact biochemical definition of ARF, as well as clear diagnostic criteria for this condition until the beginning of XXI century. More than 30 ARF definitions was found to be used in the literature [19]. In 2004, the Acute Dialysis Quality Initiative (ADQI) expert group developed for the first time a RIFLE system for the diagnosis and classification of acute renal impairment, taking into account serum creatinine level and urine excreted volume [18]. The predictive validity of the RIFLE classification has been assessed in large cohort studies conducted in the USA, Europe, and Australia; it effectively predicted hospital deaths, hospitalization the duration, renal function reverse and renal replacement therapy (RRT) need [14, 172]. The RIFLE criteria have become revolutionary as the first beyond the ARF diagnosis scope, since they have a broader view of acute renal impairment syndrome. The first attempt was made to characterize the entire spectrum of the syndrome: from minimal changes in renal function markers to RRT need.
The concept of AKI has undergone further revision over the past decade. A growing body of evidence has appeared suggesting relatively minor acute kidney injury or renal function impairment result in serious clinical consequences. Chertow et al. found that serum creatinine levels increase of >0.3 mg/dL (26.5 μmol/L) observed in 13% of 9210 hospitalized patients was independently associated with mortality rate, hospitalization duration, and treatment costs [36]. In 2007, the Acute Kidney Injury Network (AKIN) experts adjusted the RIFLE criteria to take into account small changes in serum creatinine concentration (≥26.5 μmol/L) if observed within 48 hours [117]. The same as the RIFLE, the AKIN criteria, were validated in large databases in the USA and Europe. In particular, Thakar et al. showed that the AKI severity is associated with an increased risk of death
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regardless of comorbidities: the OR for stage 1 AKI (creatinine level increase of 26.5
μmol/L or more), was 2.2, for stage 2 AKI (creatinine level 2-3-fold increase) - 6.1; for stage 3 AKI (creatinine levels more than 3 times increase or RRT need) - 8.6 [172]. Finally, in 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) working group combined the RIFLE and AKIN criteria into a single definition of acute kidney injury, and developed recommendations for the screening and management of AKI patients, using a staging-based approach. Taking into account the accumulated data on the minor renal function changes significance in hospitalized patients and associations with significant changes in early and late outcomes, the KDIGO experts postulate the importance of AKI as a clinical syndrome, along with other syndromes such as acute coronary syndrome or acute lung injury [201].
According to the current KDIGO recommendations, the AKI is defined as:
●increase in serum creatinine by ≥0.3 mg/dL (≥26.5 μmol/L) within 48 hours;
or
●increase in serum creatinine by more than 1.5 times from baseline (if known, or assumed to have occurred within the previous 7 days); or
●urine volume <0.5 mL/kg/hour for 6 hours.
One of the above criteria is enough for an AKI diagnosis.
Defining of the AKI severity stage is carried out in accordance with the following criteria:
Stage 1 - increase in serum creatinine by 1.5-1.9 times from baseline or by ≥0.3 mg/dL (≥26.5 μmol/L); excreted urine volume of <0.5 mL/kg/hour for 6-12 hours;
Stage 2 - increase in serum creatinine by 2.0-2.9 times from baseline; excreted urine volume of <0.5 mL/kg/hour for ≥12 hours;
Stage 3 - increase in serum creatinine by 3.0 times and above from baseline or up to ≥4.0 mg/dL (≥353.6 μmol/L) or RRT initiated or decrease in eGFR of <35 mL/min/1.73 m2 in patients under 18 years of age; excreted urine volume of <0.3 mL/kg/hour for ≥24 hours or anuria for ≥12 hours.
Patients should be stratified according to the worst stage criteria during the stage assignment.