Ilaria Petrucci

Long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism

Background. The effect of cinacalcet on the structural pattern of hyperplastic parathyroid glands was evaluated, using high-resolution colour Doppler (CD) sonography, in haemodialysis patients with severe, inadequately controlled, secondary hyperparathyroidism (sHPT). Methods. Nine patients (6 males, 3 females; mean age ± SD, 55.5 ± 12.6 years) received cinacalcet, with adaptation of existing concomitant therapies. Biochemical parameters and the morphology and vascular pattern of hyperplastic parathyroid glands were measured at baseline and every 6 months thereafter, for a follow-up period of 24–30 months. Results. At baseline, 28 hyperplastic glands were identified. Cinacalcet led to a reduction in glandular volume during the course of the study: 68% in glands with a baseline volume <500 mm3 and 54% in glands with a baseline volume ≥500 mm3. The mean volume ± SD of glands <500 mm3 changed significantly from the baseline (233 ± 115 mm3) to the end of follow-up (102 ± 132 mm3, P = 0.007). Levels of mean serum phosphorus, calcium and calcium–phosphorus product decreased, but not significantly, whereas there were significant decreases in mean parathyroid hormone ± SD levels (1196 ± 381 pg/ml versus 256 ± 160 pg/ml; P < 0.0001) and alkaline phosphatase ± SD levels (428 ± 294 versus 223 ± 88 IU/l; P = 0.04), accompanied by an improvement in a subjective clinical score. Conclusions. Cinacalcet, in combination with conventional treatments, led to an improvement in biochemical and clinical parameters of sHPT and reduced glandular volume in patients with severe sHPT. Volume reduction was more evident in smaller glands. Longer term, larger, randomized clinical trials are needed to confirm these preliminary findings and to further define a more systematic approach in the treatment of sHPT.

The Key Role of Color Doppler Ultrasound in the Work-up of Hemodialysis Vascular Access

Vascular access (VA) is the lifeline for the hemodialysis patient and the native arterio‐venous fistula (AVF) is the first‐choice access. Among the different tests used in the VA domain, color Doppler ultrasound (CD‐US) plays a key role in the clinical work‐up. At the present time, three are the main fields of CD‐US application: (i) evaluation of forearm arteries and veins in surgical planning; (ii) testing of AVF maturation; (iii) VA complications. Specifically, during the AVF maturation, CD‐US allows to measure the diameter and flow volume in the brachial artery and calculate the peak systolic velocity (PSV) of the arterial axis, anastomosis and efferent vein, to detect critical stenosis. The borderline stenosis, revealed by the discrepancies between access flow rate and PSV, should be followed up with subsequent tests to detect progression of stenosis; the cases with significant changes in brachial flow should be referred to angiography. In conclusion, clinical monitoring remains the backbone of any VA program. CD‐US is of utmost importance in a patient‐centered VA evaluation, because it allows the appropriate management of all aspects of VA care. These are the main reasons why we strongly advocate the adoption of a VA surveillance program based on CD‐US.

Intra-Parenchymal Renal Resistive Index Variation (IRRIV) Describes Renal Functional Reserve (RFR): Pilot Study in Healthy Volunteers

An increase of glomerular filtration rate after protein load represents renal functional reserve (RFR) and is due to afferent arteriolar vasodilation. Lack of RFR may be a risk factor for acute kidney injury (AKI), but is cumbersome to measure. We sought to develop a non-invasive, bedside method that would indirectly measure RFR. Mechanical abdominal pressure, through compression of renal vessels, decreases blood flow and activates the auto-regulatory mechanism which can be measured by a fall in renal resistive index (RRI). The study aims at elucidating the relationship between intra-parenchymal renal resistive index variation (IRRIV) during abdominal pressure and RFR. In healthy volunteers, pressure was applied by a weight on the abdomen (fluid-bag 10% of subjects body weight) while RFR was measured through a protein loading test. We recorded RRI in an interlobular artery after application of pressure using ultrasound. The maximum percentage reduction of RRI from baseline was compared in the same subject to RFR. We enrolled 14 male and 16 female subjects (mean age 38 ± 14 years). Mean creatinine clearance was 106.2 ± 16.4 ml/min/1.73 m2. RFR ranged between −1.9 and 59.7 with a mean value of 28.9 ± 13.1 ml/min/1.73 m2. Mean baseline RRI was 0.61 ± 0.05, compared to 0.49 ± 0.06 during abdominal pressure; IRRIV was 19.6 ± 6.7%, ranging between 3.1% and 29.2%. Pearsons coefficient between RFR and IRRIV was 74.16% (p < 0.001). Our data show the correlation between IRRIV and RFR. Our results can lead to the development of a “stress test” for a rapid screen of RFR to establish renal susceptibility to different exposures and the consequent risk for AKI.

Ultrasound in clinical setting of secondary hyperparathyroidism.

Secondary hyperparathyroidism (sHPT) is one of the most common and serious complications of chronic kidney disease (CKD) and maintenance hemodialysis (MHD). In sHPT, the biology of parathyroid cells changes significantly toward diffuse and nodular hyperplasia. Diagnosis and treatment of sHPT are based on intact parathyroid hormone (i-PTH) serum levels and on the parameters of mineral metabolism. The morphological diagnosis of sHPT relies on 2 complementary imaging techniques: high-resolution ultrasonography with color Doppler imaging (US/CD) and 99mTc-methoxyisobutylisonitrile (MIBI) scintigraphy. The main objective of this review is to stimulate nephrologists to use US/CD of the parathyroid glands during the progression of CKD in order to aid clinical, pharmacological and surgical strategies. The primary role of US/CD in sHPT should be to integrate the clinical diagnosis by defining the number and volume of hyperplastic glands, although the international guidelines do not state when and why to perform US/CD. This review also evaluates the role of US/CD in clinical follow-up and assessment of therapeutic response of sHPT, and it highlights how US/CD can evaluate the effect of therapy with phosphate binders, vitamin D or its analogues and calcimimetics, which are changing the natural history of sHPT and the frequency of parathyroidectomy. Evaluation of the morphological and vascular changes of hyperplastic parathyroids is useful to guide percutaneous ethanol injection therapy and to support clinical, pharmacological and surgical strategies. Epidemiological studies are needed to establish how US/CD could change the management of sHPT and why it should be repeated in patients with high levels of serum i-PTH.

Presurgical Setting of Secondary Hyperparathyroidism Using High-Resolution Sonography and Color Doppler.

PURPOSE High-resolution sonography (US) with color Doppler imaging (CDI) is a simple, noninvasive, safe and repeatable technique able to highlight the presence of hyperplastic parathyroid glands and changes in their volume, structure, and vascularization during uremia. The primary aim of this study was to assess the diagnostic accuracy of US and the sensitivity for localizing parathyroid glands with a volume ≥ 500 mm(3). The secondary aim was to assess the parameters that define parathyroid glandular perfusion. MATERIALS AND METHODS The diagnostic use of US was assessed in 40 consecutive uremic patients with severe secondary hyperparathyroidism (sHPT) who were receiving maintenance hemodialysis or conservative therapy with a hypoproteic-hypophosphoric diet and had undergone parathyroidectomy. Prior to surgery (99m)TC-sestamibi scintigraphy (SM) was performed in all patients. RESULTS The sensitivity, specificity, positive predictive value and accuracy of US were 74 %, 75 %, 98 %, and 74 %, respectively. The sensitivity for localizing glands with a volume ≥ 500 mm(3) was 90 %. US and SM had a combined sensitivity of 83 %. The vascularization of parathyroid glands became more evident with increasing glandular volume. With CDI, the signs of hypervascularization (i. e. an enlarged feeding artery at the hilum, a peripheral arc of vascularity and/or ray-like endonodular vessels) were present in 77 % of glands with a volume ≥ 500 mm(3). CONCLUSION The sensitivity of US is higher than that of SM, but it cannot be compared with that of parathyroidectomy (74 vs. 95 %). However, US/CDI is able to characterize glands with different volumes and vascular patterns. Since glandular volume and vascularization are indicative of the severity of sHPT, this study suggests that the main role of US/CDI in the setting of sHPT should be to complete the diagnosis and to evaluate the morphological changes of enlarged glands during uremia in order to define surgical timing, rather than to assess the presurgical location of glands.

Use of Ultrasound to Assess the Response to Therapy for Secondary Hyperparathyroidism

Secondary hyperparathyroidism (SHPT) is a common complication in patients with chronic kidney disease. In SHPT, the biology of parathyroid cells changes significantly toward diffuse nodular hyperplasia. Currently, diagnosis of SHPT is based on intact parathyroid hormone serum levels and parameters of mineral metabolism. The morphologic diagnosis of SHPT relies on high-resolution ultrasonography with color Doppler imaging. This report describes a maintenance hemodialysis patient with severe SHPT treated using conventional therapy (phosphate binders and oral/intravenous vitamin D or analogues) and the subsequent addition of a calcimimetic. The role of color Doppler ultrasonography in the diagnosis, clinical follow-up, and assessment of therapeutic response of SHPT is discussed. This case suggests that the availability of calcimimetics has changed the natural history of clinical SHPT and may change the therapeutic utility of parathyroidectomy. Use of color Doppler ultrasonography further supports these therapeutic advances, allowing evaluation of the morphologic and vascular changes in hyperplastic parathyroid glands and aiding clinical, pharmacologic, and surgical strategies.

Imaging in Chronic Kidney Disease.

Chronic kidney disease (CKD) diagnosis and staging are based on estimated or calculated glomerular filtration rate (GFR), urinalysis and kidney structure at renal imaging techniques. Ultrasound (US) has a key role in evaluating both morphological changes (by means of B-Mode) and patterns of vascularization (by means of color-Doppler and contrast-enhanced US), thus contributing to CKD diagnosis and to the follow-up of its progression. In CKD, conventional US allows measuring longitudinal diameter and cortical thickness and evaluating renal echogenicity and urinary tract status. Maximum renal length is usually considered a morphological marker of CKD, as it decreases contemporarily to GFR, and should be systematically recorded in US reports. More recently, it has been found to be a significant correlation of both renal longitudinal diameter and cortical thickness with renal function. Conventional US should be integrated by color Doppler, which shows parenchymal perfusion and patency of veins and arteries, and by spectral Doppler, which is crucial for the diagnosis of renal artery stenosis and provides important information about intrarenal microcirculation. Different values of renal resistive indexes (RIs) have been associated with different primary diseases, as they reflect vascular compliance. Since RIs significantly correlate with renal function, they have been proposed to be independent risk factors for CKD progression, besides proteinuria, low GFR and arterial hypertension. Despite several new applications, US and color Doppler contribute to a definite diagnosis in <50% of cases of CKD, because of the lack of specific US patterns, especially in cases of advanced CKD. However, US is useful to evaluate CKD progression and to screen patients at risk for CKD. The indications and the recommended frequency of color Doppler US could differ in each case and the follow-up should be tailored.

Clinical Scenarios in Chronic Kidney Disease: Vascular Chronic Diseases.

Vascular chronic diseases represent one of the leading causes of end-stage renal disease in incident dialysis patients. B-Mode ultrasound (US) and color Doppler (CD) have a high sensitivity and specificity in the diagnosis of vascular chronic diseases. US and CD should be used to identify subjects in the high risk population who are affected by main renal artery stenosis (RAS) and to identify and characterize patients without RAS who have chronic ischemic nephropathy caused by nephroangiosclerosis and/or atheroembolic disease. The most important CD parameters in the work-up of suspected RAS are increased peak systolic velocity and diastolic velocity, spectral broadening, high renal:aortic ratio and lateralization of renal resistive indexes (RIs). In the absence of direct or indirect signs of RAS, increases in intraparenchymal RIs, associated with systemic atherosclerotic disease, are indicative of microcirculation damage related to nephroangiosclerosis or atheroembolic disease.

Clinical Scenarios in Acute Kidney Injury: Post-Renal Acute Kidney Injury

The incidence of acute kidney injury related to urinary tract obstruction is low (1-10%). It occurs in bilateral renal or lower urinary tract obstruction or in ureter obstruction in patients with a single functioning kidney or with pre-existing chronic kidney disease. The etiology and the incidence of obstruction vary on the basis of age and gender. Conventional ultrasound has a high sensitivity (>95%), but low specificity (<70%) in the diagnosis of urinary tract obstruction. Nevertheless, color Doppler is used through the evaluation of renal resistive indexes, ureteral jet and twinkling artifact.

Clinical Scenarios in Acute Kidney Injury: Parenchymal Acute Kidney Injury-Tubulo-Interstitial Diseases.

Acute tubular necrosis (ATN) is the most common type of acute kidney injury (AKI) related to parenchymal damage (90% of cases). It may be due to a direct kidney injury, such as sepsis, drugs, toxins, contrast media, hemoglobinuria and myoglobinuria, or it may be the consequence of a prolonged systemic ischemic injury. Conventional ultrasound (US) shows enlarged kidneys with hypoechoic pyramids. Increased volume is largely sustained by the increase of anteroposterior diameter, while longitudinal axis usually maintains its normal length. Despite the role of color Doppler in AKI still being debated, many studies demonstrate that renal resistive indexes (RIs) vary on the basis of primary disease. Moreover, several studies assessed that higher RI values are predictive of persistent AKI. Nevertheless, due to the marked heterogeneity among the studies, further investigations focused on timing of RI measurement and test performances are needed. Acute interstitial nephritis is also a frequent cause of AKI, mainly due to non-steroidal anti-inflammatory drugs and antibiotics administration. The development of acute interstitial nephritis is due to an immunological reaction against nephritogenic exogenous antigens, processed by tubular cells. In acute interstitial nephritis, as well as in ATN, conventional US does not allow a definitive diagnosis. Kidneys appear enlarged and widely hyperechoic due to interstitial edema and inflammatory infiltration. Also, in this condition, hemodynamic changes are closely correlated to the severity and the progression of the anatomical damage.