L.J. Schultze Kool

Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism.

Context Primary aldosteronism can involve 1 or both adrenal glands. Surgery is indicated only for unilateral disease. Experts prefer adrenal vein sampling (AVS) to localize the source, but many physicians rely on computed tomography (CT) or magnetic resonance imaging (MRI). Content The authors reviewed 38 studies that compared localization by CT/MRI and AVS. In 37.8% of 950 patients, CT/MRI results disagreed with AVS results. Based on CT/MRI alone, the following would have occurred: surgery for bilateral disease in 14.6% of patients, medical treatment for unilateral disease in 19.1%, and removal of the wrong adrenal in 3.9%. Caution Long-term outcomes, the best indicator of success, were often missing. Implication Because CT/MRI is not reliable, AVS is preferred for staging primary aldosteronism. The Editors Although debate on the true prevalence of primary aldosteronism among the hypertensive population continues, primary aldosteronism is considered a frequent and curable form of hypertension. Depending on the population tested and the tools used to confirm the diagnosis, primary aldosteronism is reported to occur in approximately 5% to 13% of hypertensive patients, predominantly those with severe hypertension (18). Because patients with unilateral adrenal hypersecretion of aldosterone may be cured by unilateral adrenalectomy, differentiating unilateral (most often an adenoma) from bilateral (most often bilateral hyperplasia) aldosterone hypersecretion is important. In patients with bilateral hypersecretion, medical treatment, usually mineralocorticoid-receptor antagonists, is the therapy of choice. In the late 1960s, adrenal vein sampling (AVS) was introduced as a test to distinguish unilateral from bilateral primary aldosteronism (9). Later, computed tomography (CT) and magnetic resonance imaging (MRI) were adopted as the primary procedures with which to differentiate unilateral from bilateral adrenal abnormalities. In a considerable proportion of patients, however, CT and MRI results were found to disagree with those of AVS; CT/MRI would show, for example, a unilateral abnormal adrenal gland when aldosterone hypersecretion actually was occurring in the contralateral gland or bilaterally, or would show bilateral normal or abnormal adrenal glands when aldosterone hypersecretion was occurring in only 1 gland (1014). A recent prospective study of 203 patients showed that operative planning based on anatomical imaging alone would have inappropriately excluded 21.7% of patients from adrenalectomy and would have led to unnecessary sugery in 24.7% (15). Thus, in recent years, AVS has regained popularity. Almost all experts agree that the criterion standard diagnostic test for lateralization of aldosterone secretion is measurement of aldosterone levels in the adrenal veins through AVS (11, 12, 1620). However, AVS has not replaced CT/MRI because it is not universally available and CT/MRI helps the surgeon to accurately localize the adrenal gland. In addition, AVS is a complicated technique with a relatively high chance of procedural failure (for example, when an adrenal vein cannot be adequately cannulated) in inexperienced hands and is more invasive than CT/MRI. Many physicians therefore perform CT/MRI as the first and sometimes only investigation to diagnose laterality of aldosterone secretion. Because misinterpretation of the imaging results could lead to inappropriate treatment, it is essential to know, under the assumption that AVS is the criterion standard test, how often inappropriate treatment decisions would have been made on the basis of CT/MRI findings alone. We performed a systematic literature search and analyzed studies of patients who underwent both techniques. Methods Data Sources and Searches We conducted a systematic search of PubMed, MEDLINE, and EMBASE to find English-, French-, German-, or Dutch-language studies on primary aldosteronism by using the following search terms: ((primary hyperaldosteronism) OR (primary aldosteronism) OR (Conn) OR (hyperaldosteronism) OR (aldosterone-producing adenoma) OR (APA) OR (idiopathic hyperaldosteronism) OR (IHA) OR (primary adrenal hyperplasia) OR (PAH) OR (bilateral adrenal hyperplasia) OR (BAH)) AND ((adrenal venous sampling) OR (AVS) OR (venous sampling) OR (vein sampling) OR (adrenal vein) OR (adrenal venous)). We searched the Cochrane Library using the search string primary hyperaldosteronism or hyperaldosteronism and AVS or adrenal venous sampling for clinical trials published in English, French, German, or Dutch. Searches are up to date through April 2009. We sought to include all studies that performed both AVS and CT/MRI. We assumed that articles that reported on AVS results would also report on CT/MRI findings because CT/MRI is the standard imaging study in patients with primary aldosteronism. Study Selection Two reviewers independently and in duplicate assessed the eligibility of all abstracts. We excluded abstracts if they represented reviews or practice guidelines or if they, with certainty, described only studies in animals or children; patients without primary aldosteronism; or only 1 patient. If we could not make a decision about inclusion solely on the basis of the abstracts, we retrieved and reviewed full-text articles. We considered studies eligible for inclusion if they met the following criteria: 1) original reported results, not previously published or used in earlier studies; 2) adult patients (age> 18 years) with a diagnosis of primary aldosteronism; 3) description of more than 1 patient to avoid publication bias (when only 1 patient is described, there is a high a priori chance that the findings in this patient were unusual, which could imply that such studies are more likely to contain results in which CT/MRI did not agree with AVS results); 4) CT/MRI plus bilateral selective AVS performed in all patients, with the results of both investigations reported; and 5) publication from 1977 onward (CT has been available since that year). We excluded articles if 1) data had already been published (only the most recent publication was used), 2) inclusion bias was suspected because patients with concordant results seemed to have been selectively included or because selective examples of concordant and discordant CT/MRI and AVS results were presumed to have been given, and 3) only discordant results were described. To ensure interobserver consistency, differences in interpretation were resolved by consensus of the 2 reviewers, by group conferences with the other authors, or by referencing the original full-text article. Data Extraction and Quality Assessment We made a database of all studies eligible for inclusion. For each eligible study, we recorded aggregated results for the patients for whom the study reported the following: CT/MRI and AVS results; the techniques of CT, MRI, and AVS (such as slice thickness of the CT/MRI images); use of synthetic adrenocorticotropic hormone (ACTH) during AVS; and the AVS criteria used to determine whether aldosterone secretion was lateralized. For the 950 patients whose CT/MRI and AVS results could be retrieved, we recorded such characteristics as age, sex, blood pressure, and serum potassium level and biochemical variables (such as criteria for diagnosis of primary aldosteronism), as well as treatment strategy and patient follow-up if we could link those characteristics with certainty to these patients. Because the diagnostic criteria for primary aldosteronism differ in their stringency, we subdivided the articles by whether the diagnosis of primary aldosteronism was based on a sodium chloride loading test (the most stringent criterion) or on the aldosteronerenin ratio (less stringent criterion) or plasma aldosterone concentration plus plasma renin activity or plasma renin concentration (less stringent criterion). We also evaluated whether the report mentioned the cutoff value of both the selectivity criterion and the lateralization criterion. The selectivity criterion is used to determine whether blood was drawn selectively from the adrenal veins and not from an adjacent vein; this ratio is calculated for both the left and the right side and is expressed as the CAV/CIVC ratio: [cortisol]adrenal vein/[cortisol]inferior vena cava; when this ratio exceeds a certain arbitrary cutoff value, sampling can be considered selective. The lateralization criterion is used to determine whether aldosterone hypersecretion was unilateral or bilateral by comparing aldosterone and cortisol concentrations in the 2 adrenal veins; this ratio, A/Cips/ACcont, is calculated as [aldosterone]/[cortisol]ipsilateral adrenal vein/[aldosterone]/[cortisol]contralateral adrenal vein (the ipsilateral adrenal vein is the one with the highest [aldosterone]/[cortisol] ratio). When this ratio exceeds a certain arbitrary cutoff value, aldosterone secretion is recorded as lateralized. When we were uncertain about how the authors confirmed the diagnosis of primary aldosteronism, we contacted one of the contributing authors to ask for details about the measurement of aldosterone and renin and whether a sodium chloride loading test had been performed. We also contacted the authors when the article did not specify the criteria used during AVS; of the 31 authors contacted, 22 (71%) responded and 13 (59% of the responders) could provide us with additional information. We excluded articles in which we could not confirm that the authors based the diagnosis of primary aldosteronism on a sodium chloride loading test, aldosteronerenin ratio, or plasma aldosterone concentration plus plasma renin activity. Twenty-one articles reported on the success rate of AVS. Of the 976 procedures performed, 183 were unsuccessful (overall success rate, 81.3%). Data Synthesis and Analysis Assuming AVS is the diagnostic reference criterion test, we analyzed how many times the CT/MRI result agreed or disagreed with the AVS result. The CT/MRI result was considered accurate

Adrenal nodularity and somatic mutations in primary aldosteronism: One node is the culprit?

CONTEXTnSomatic mutations in genes that influence cell entry of calcium have been identified in aldosterone-producing adenomas (APAs) of adrenal cortex in primary aldosteronism (PA). Many adrenal glands removed for suspicion of APA do not contain a single adenoma but nodular hyperplasia.nnnOBJECTIVEnThe objective of the study was to assess multinodularity and phenotypic and genotypic characteristics of adrenals removed because of the suspicion of APAs.nnnDESIGN AND METHODSnWe assessed the adrenals of 53 PA patients for histopathological characteristics and immunohistochemistry for aldosterone (P450C18) and cortisol (P450C11) synthesis and for KCNJ5, ATP1A1, ATP2B3, and CACNA1D mutations in microdissected nodi.nnnRESULTSnGlands contained a solitary adenoma in 43% and nodular hyperplasia in 53% of cases. Most adrenal glands contained only one nodule positive for P450C18 expression, with all other nodules negative. KCNJ5 mutations were present in 22 of 53 adrenals (13 adenoma and nine multinodular adrenals). An ATP1A1 and a CACNA1D mutation were found in one multinodular gland each and an ATP2B3 mutation in five APA-containing glands. Mutations were always located in the P450C18-positive nodule. In one gland two nodules containing two different KCNJ5 mutations were present. Zona fasciculata-like cells were more typical for KCNJ5 mutation-containing nodules and zona glomerulosa-like cells for the other three genes.nnnCONCLUSIONSnSomatic mutations in KCNJ5, ATP1A1, or CACNA1D genes are not limited to APAs but are also found in the more frequent multinodular adrenals. In multinodular glands, only one nodule harbors a mutation. This suggests that the occurrence of a mutation and nodule formation are independent processes. The implications for clinical management remain to be determined.

Acute Arterial Occlusion after Deployment of the Angio-Seal Closure Device: Is it as Uncommon as we Think?

Angio-Seal is a frequently used vascular closure device after arterial catheterisation. Major complications are infrequently reported. We present four cases occurring within a 2-month period in our hospital with dislodgement of an Angio-Seal causing acute arterial occlusion, resulting in loss of limb in one case. Surgical intervention was necessary in all cases. Acute arterial occlusion after deployment of the Angio-Seal in patients with peripheral arterial disease might be less uncommon than the literature suggests.

Simplifying post-EVAR surveillance.

Surveillance after endovascular aneurysm repair (EVAR) is costly and a burden for the patient. Imaging is performed to detect stent-graft failure from endoleak or haemodynamic obstruction. Presently, computed tomographic angiography (CTA) is considered the gold standard for post-EVAR surveillance, as it has the potential to visualise most threats to stent-graft durability, such as migration, kinking, structural disintegration, endoleaks and aneurysm growth. Serious drawbacks of serial CTA, apart from its costs, are the risks of contrast-induced nephropathy and carcinogenesis from cumulative radiation exposure. Therefore, less invasive surveillance imaging techniques have been introduced, although none of these individually offers the ability to visualise all of the above signs of stent-graft failure. In the present observational study, Harrison and coworkers retrospectively investigated the results of a change in EVAR follow-up, replacing their original extensive protocol of serial, single-arterial-phase CTA, duplex ultrasound (DUS) and plain abdominal radiography (AXR) by the combination of DUS and AXR, with CTA performed only when problems were identified or DUS was not diagnostic. After a 4-year-period with 412 annual imaging sets in a series of 194 patients, the cumulative freedom of CTA was 65%. Eighteen out of 30 abnormalities found with the DUSeAXR combination were reconfirmed by CTA, resulting in a positive predictive value of 60%. In absence of a control

Quality of Life in Primary Aldosteronism: a Comparative Effectiveness Study of Adrenalectomy and Medical Treatment.

ContextnIn primary aldosteronism (PA), two subtypes are distinguished: aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). In general, these are treated by adrenalectomy (ADX) and mineralocorticoid receptor antagonists (MRA), respectively.nnnObjectivenTo compare the effects of surgical treatment and medical treatment on quality of life (QoL).nnnDesignnPost hoc comparative effectiveness study within the Subtyping Primary Aldosteronism: A Randomized Trial Comparing Adrenal Vein Sampling and Computed Tomography Scan (SPARTACUS) trial.nnnSettingnTwelve Dutch hospitals and one Polish hospital.nnnParticipantsnPatients with PA (n = 184).nnnInterventionsnADX or MRAs.nnnMain Outcome MeasuresnAt baseline and 6-month and 1-year follow-up, we assessed QoL by two validated questionnaires: RAND 36-Item Health Survey 1.0 (RAND SF-36) and European Quality of Life-5 Dimensions (EQ-5D).nnnResultsnAt baseline, seven of eight RAND SF-36 subscales and both summary scores, as well as three of five EQ-5D dimensions and the visual analog scale, were lower in patients with PA compared with the general population, especially in women. The beneficial effects of ADX were larger than for MRAs for seven RAND SF-36 subscales, both summary scores, and health change. For the EQ-5D, we detected a difference in favor of ADX in two dimensions and the visual analog scale. Most differences in QoL between both treatments exceeded the minimally clinically important difference. After 1 year, almost all QoL measures had normalized for adrenalectomized patients. For patients on medical treatment, most QoL measures had improved but not all to the level of the general population.nnnConclusionnBoth treatments improve QoL in PA, underscoring the importance of identifying these patients. QoL improved more after ADX for suspected APA than after initiation of medical treatment for suspected BAH.

Enzyme Prodrug Therapy Achieves Site-Specific, Personalized Physiological Responses to the Locally Produced Nitric Oxide

Nitric oxide (NO) is a highly potent but short-lived endogenous radical with a wide spectrum of physiological activities. In this work, we developed an enzymatic approach to the site-specific synthesis of NO mediated by biocatalytic surface coatings. Multilayered polyelectrolyte films were optimized as host compartments for the immobilized β-galactosidase (β-Gal) enzyme through a screen of eight polycations and eight polyanions. The lead composition was used to achieve localized production of NO through the addition of β-Gal–NONOate, a prodrug that releases NO following enzymatic bioconversion. The resulting coatings afforded physiologically relevant flux of NO matching that of the healthy human endothelium. The antiproliferative effect due to the synthesized NO in cell culture was site-specific: within a multiwell dish with freely shared media and nutrients, a 10-fold inhibition of cell growth was achieved on top of the biocatalytic coatings compared to the immediately adjacent enzyme-free microwells. The physiological effect of NO produced via the enzyme prodrug therapy was validated ex vivo in isolated arteries through the measurement of vasodilation. Biocatalytic coatings were deposited on wires produced using alloys used in clinical practice and successfully mediated a NONOate concentration-dependent vasodilation in the small arteries of rats. The results of this study present an exciting opportunity to manufacture implantable biomaterials with physiological responses controlled to the desired level for personalized treatment.

Preoperative CT-Angiography Predicts Ex Vivo Vein Length for Right Kidneys After Laparoscopic Donor Nephrectomy.

BACKGROUND Implantation of a kidney with a short renal vein is technically more challenging and therefore prone for technique-related complications. It remains unclear whether pre-operative computed tomography angiography (CTA), to assess vascular anatomy of the donor kidney, can be used to predict renal vein length. MATERIAL AND METHODS Right and left renal vein lengths of 100 consecutive kidney donors were measured in an oblique-coronal plane multiplanar reconstruction image of 100 consecutive kidney donors in whom ex vivo vein length was measured after recovery. In a second retrospective cohort of 100 consecutive kidney donors donating a right kidney, preoperative CTA vein length measurements were correlated to anastomosis time and early graft outcome. RESULTS Left and right renal vein lengths, measured on CTA, were 43.2 mm and 30.0 mm, respectively. No correlation was found between CTA and ex vivo measurements for the left renal vein (p=.610), whereas a significant correlation was found for the right renal vein (p=.021). In the retrospective cohort, right renal vein length was significantly correlated with the anastomosis time but not with early graft outcome. CONCLUSIONS The length of the right, but not the left, renal vein can be predicted by preoperative CTA, but this does not hold true for the left renal vein.

Pasireotide does not improve efficacy of aspiration sclerotherapy in patients with large hepatic cysts, a randomized controlled trial

ObjectivesWe tested whether complementary use of the somatostatin analogue pasireotide would augment efficacy of aspiration sclerotherapy of hepatic cysts.MethodsWe conducted a double-blind, placebo-controlled trial in patients who underwent aspiration sclerotherapy of a large (>5 cm) symptomatic hepatic cyst. Patients were randomized to either intramuscular injections of pasireotide 60 mg long-acting release (nxa0=xa017) or placebo (sodium chloride 0.9 %, nxa0=xa017). Injections were administered 2 weeks before and 2 weeks after aspiration sclerotherapy. The primary endpoint was proportional cyst diameter reduction (%) from baseline to 6 weeks. Secondary outcomes included long-term cyst reduction at 26 weeks, patient-reported outcomes including the polycystic liver disease-questionnaire (PLD-Q) and safety.ResultsThirty-four patients (32 females; 53.6xa0±xa07.8 years) were randomized between pasireotide or placebo. Pasireotide did not improve efficacy of aspiration sclerotherapy at 6 weeks compared to controls (23.6 % [IQR 12.6–30.0] vs. 21.8 % [9.6–31.8]; pxa0=xa00.96). Long-term cyst diameter reduction was similar in both groups (49.1 % [27.0–73.6] and 45.6 % [29.6–59.6]; pxa0=xa00.90). Mean PLD-Q scores improved significantly in both groups (pxa0<xa00.01) without differences between arms (p =xa00.92).ConclusionsIn patients with large symptomatic hepatic cysts, complementary pasireotide to aspiration sclerotherapy did not improve cyst reduction or clinical response.Key Points• Complementary pasireotide treatment does not improve efficacy of aspiration sclerotherapy.• Cyst fluid reaccumulation after aspiration sclerotherapy is a transient phenomenon.• Aspiration sclerotherapy strongly reduces symptoms and normalizes quality of life.

Diagnostic quality of time-averaged ECG-gated CT data

Purpose: ECG-gated CTA allows visualization of the aneurysm and stentgraft during the different phases of the cardiac cycle, although with a lower SNR per cardiac phase than without ECG gating using the same dose. In our institution, abdominal aortic aneurysm (AAA) is evaluated using non-ECG-gated CTA. Some common CT scanners cannot reconstruct a non-gated volume from ECG-gated acquired data. In order to obtain the same diagnostic image quality, we propose offline temporal averaging of the ECG-gated data. This process, though straightforward, is fundamentally different from taking a non-gated scan, and its result will certainly differ as well. The purpose of this study is to quantitatively investigate how good off-line averaging approximates a non-gated scan. Method: Non-gated and ECG-gated CT scans have been performed on a phantom (Catphan 500). Afterwards the phases of the ECG-gated CTA data were averaged to create a third dataset. The three sets are compared with respect to noise properties (NPS) and frequency response (MTF). To study motion artifacts identical scans were acquired on a programmable dynamic phantom. Results and Conclusions: The experiments show that the spatial frequency content is not affected by the averaging process. The minor differences observed for the noise properties and motion artifacts are in favor of the averaged data. Therefore the averaged ECG-gated phases can be used for diagnosis. This enables the use of ECG-gating for research on stentgrafts in AAA, without impairing clinical patient care.

Self-expandable tubular collagen implants

Collagen has been extensively used as a biomaterial, yet for tubular organ repair, synthetic polymers or metals (e.g., stents) are typically used. In this study, we report a novel type of tubular implant solely consisting of type I collagen, suitable to self‐expand in case of minimal invasive implantation. Potential benefits of this collagen scaffold over conventional materials include improved endothelialization, biodegradation over time, and possibilities to add bioactive components to the scaffold, such as anticoagulants. Implants were prepared by compression of porous scaffolds consisting of fibrillar type I collagen (1.0–2.0% (w/v)). By applying carbodiimide cross‐linking to the compressed scaffolds in their opened position, entropy‐driven shape memory was induced. The scaffolds were subsequently crimped and dried around a guidewire. Upon exposure to water, crimped scaffolds deployed within 15–60 s (depending on the collagen concentration used), thereby returning to the original opened form. The scaffolds were cytocompatible as assessed by cell culture with human primary vascular endothelial and smooth muscle cells. Compression force required to compress the open scaffolds increased with collagen content from 16 to 32 mN for 1.0% to 2.0% (w/v) collagen scaffolds. In conclusion, we report the first self‐expandable tubular implant consisting of solely type I collagen that may have potential as a biological vascular implant.