Società Italiana di Pediatria Federazione Italiana Medici PediatriUfficio Centrale per la Qualità GSAQ Gruppo di Studioper l'Accreditamento e la Qualità GPCPGruppo Pediatria delle Cure Primarie MANUALE DI QUALITÀPER LA PEDIATRIA DIFAMIGLIA a cura diLuigi Greco con la collaborazione diLeonello Venturelli, Mariarosaria Filograna
Dans la pharmacie en ligne Viagra-représenté Paris large éventail de la dysfonction érectile anti-plus consommée. Générique Levitra (vardenafil), Cialis (tadalafil) et achat viagra pour homme, dont le prix est acceptable pour tous les budgets.1
En internet farmacia empecé a pedir porque en la farmacia de al lado nunca había deseado surtido de medicamentos propecia sin receta Muy cómodo en el uso de la farmacia. Estuvimos en el restaurante a. aquí la tableta con la entrega en el lugar de.
NDT Advance Access published May 20, 2010
Nephrol Dial Transplant (2010) 1 of 8doi: 10.1093/ndt/gfq259 Non-invasive investigations of potential renal artery stenosis in renalinsufficiency Per Eriksson1,2, Ahmed Abdulilah Mohammed3,4, Jakob De Geer3,4, Johan Kihlberg4,5,Anders Persson3,5, Göran Granerus6, Fredrik Nyström7 and Örjan Smedby3,4,5 1Nephrology (IMH), Linköping University, Sweden, 2Department of Nephrology, University Hospital, Linköping, Sweden,3Radiology (IMH), Linköping University, Sweden, 4Department of Radiology, University Hospital, Linköping, Sweden, 5Center for Medical Image Science and Visualization (CMIV), Linköping University, Sweden, 6Clinical Physiology (IMH), Linköping University,Sweden and 7Internal Medicine (IMH), Linköping University, Sweden Correspondence and offprint requests to: Örjan Smedby; E-mail: firstname.lastname@example.org Keywords: computed tomography angiography; magnetic resonance angiography; renal artery stenosis; renography; ultrasound Background. The diagnostic value of non-invasive meth-ods for diagnosing renal artery stenosis in patients with re-nal insufficiency is incompletely known.
Methods. Forty-seven consecutive patients with moderate-ly impaired renal function and a clinical suspicion of renalartery stenosis were investigated with computed tomogra- There is debate over how to investigate renal artery steno- phy angiography (CTA), gadolinium-enhanced magnetic sis (RAS), in particular how to determine whether, and to resonance angiography (MRA), contrast-enhanced Dopp- what extent, this contributes to renovascular hypertension.
ler ultrasound and captopril renography. The primary ref- Presently, there is not much data that speak in favour of a erence standard was stenosis reducing the vessel diameter liberal use of percutaneous transluminal renal angioplasty by at least 50% on CTA, and an alternative reference stan- (PTRA) in uncomplicated cases of renal artery stenosis dard (‘morphological and functional stenosis') was de- Even less is known about how to investigate and treat f ined as at least 50% diameter reduction on CTA or patients with renal failure and suspected renal artery steno- MRA, combined with a positive finding from ultrasound sis. Ischaemic nephropathy has been defined as ‘impair- or captopril renography.
ment of renal function beyond occlusive disease of the Results. The frequency of positive findings, calculated on main renal arteries' , stressing that reduced blood flow the basis of individual patients, was 70% for CTA, 60% for may not be the sole or even the major contributor to re- FOR PERSONAL USE ONLY MRA, 53% for ultrasound and 30% for captopril renogra- duced renal function. Angiotensin II, endothelin-1, TGF- phy. Counting kidneys rather than patients, corresponding β and PDGF-β are some of the actors that may participate frequencies were 53%, 41%, 29% and 15%, respectively.
in the process of building extracellular matrix and collagen In relation to the CTA standard, the sensitivity (and spec- IV in the renal interstitium In one study, the 2-year cu- ificity) at the patient level was 0.81 (0.79) for MRA, 0.70 mulative incidence of renal atrophy assessed with duplex (0.89) for ultrasound and 0.42 (1.00) for captopril renog- ultrasound scanning was 6% in patients with normal renal raphy, and at the kidney level 0.76 (0.82), 0.53 (0.81) and arteries, 12% if <60% stenosis, and 21% if at least 60% 0.30 (0.86), respectively. Relative to the alternative refer- stenosis . Using duplex ultrasonography and renal scin- ence standard, corresponding values at the patient level tigraphy in all patients, renal biopsy in 40% and renal an- were 1.00 (0.62) for CTA, 0.90 (0.69) for MRA, 0.91 giography in 25%, a carefully performed study of 56 (1.00) for ultrasound and 0.67 (1.00) for captopril renog- consecutive patients with a presumed diagnosis of nephro- raphy, and at the kidney level 0.96 (0.76), 0.85 (0.79), 0.71 sclerosis found atheromatous renovascular disease in 34% (0.97) and 0.50 (0.97), respectively.
of cases and ‘true' hypertensive nephrosclerosis in only Conclusions. CTA and MRA are superior to ultrasound 46% . The intensity and mode of lipid lowering therapy and captopril renography at diagnosing morphological ste- may influence intima-media thickness in atherosclerosis nosis, but ultrasound may be useful as a screening method , and it is hoped that more accurate diagnosis of and captopril renography for verifying renin-dependent ischaemic nephropathy, distinguishing between small ves- sel and large vessel disease, would stimulate development The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: email@example.com P. Eriksson et al.
of new medical strategies against atherosclerotic and fi- abetes, other kidney disease than presumed nephrosclerosis, hypersensi- brotic mechanisms in the kidney. Furthermore, a conve- tivity to radiologic contrast agents, pregnancy/lactation, use of pacemaker, nient and inexpensive method for diagnosing ischaemic contagious diseases and known malignancy. Patients judged not to toler-ate withdrawal of ACE inhibitors or angiotensin II receptor antagonists for nephropathy could also prevent other diagnostic proce- 7 days prior to the investigations and/or unable to hold their breath for dures with potential risks, e.g. renal biopsy in patients with 15 s were also not eligible for the study.
proteinuria. The point of detecting RAS is thus not only to The patients were investigated starting at about 9:00 a.m. on Day 1 by find patients suitable for PTRA but also to characterize the blood sampling for analysis of routine laboratory parameters and a check- nature of kidney disease eventually facilitating medical up by the responsible physician. They proceeded by undergoing baselinerenography after initiation of intravenous infusion of 0.9% NaCl. Ultra- therapy. In the former situation, the specificity of the meth- sound and magnetic resonance imaging (MRI) examination were per- od is important, whereas higher sensitivity may be pre- formed immediately after the renography, and the administration of ferred on other occasions.
NaCl continued until the patient was provided with lunch. Then, CTA Renography has long been a useful tool in the functional was performed, and intravenous saline infusion continued during another12 h. Day 2 began withdrawing of blood in the fasting state and included evaluation of RAS [However, the method is said to be re-analysis of serum creatinine. The patients then underwent the second less accurate when used in patients with impaired renal renographic examination after pre-treatment with captopril. Patients in function. The other major technique to functionally evalu- whom the serum creatinine had not increased >15% were allowed to re- ate renal artery stenosis is to use ultrasound with Doppler turn home after lunch on Day 2 after a final check-up by the responsible analysis of the blood flow in the artery, where stenosis is typically accompanied by an increase in peak systolic ve-locity (PSV) [This method has become more feasi- ble since non-toxic contrast media that increase the During the time period December 2004–October 2006, 27 patients sensitivity have emerged [For non-invasive morpho- were examined with a multidetector row CT scanner (Somatom Sensa-tion16; Siemens Medical Systems, Forcheim, Germany) by injecting logical imaging of the vasculature, the clinician can choose 50 mL iodixanol 320 mg I/mL (Visipaque®, GE Healthcare, Princeton, between computed tomography angiography (CTA)  NJ, USA) at 5.5 mL/s, followed by a saline bolus (70 mL, 5.5 mL/s). Au- and magnetic resonance angiography (MRA) , both tomatic bolus triggering was used. An early arterial phase (16 × 0.75 mm of which give high-resolution images but also involve the collimation, slice width 1.0 mm, reconstruction interval 0.4 mm, mean use of contrast media.
120 mAs, 120 kV) was acquired. During the time period November2006–February 2008, 20 patients were examined with a dual-source multi- The question of ‘gold standard' for assessment of arterial detector row CT scanner (Somatom Definition; Siemens Medical Systems, stenoses is complicated. Invasive catheter angiography has Forcheim, Germany) with contrast injection as described above. An early been used for a long time and can be combined with mea- arterial phase (64 × 0.65 mm collimation, slice width 0.75 mm, reconstruc- surement of the pressure drop across the stenosis , tion interval 0.3 mm, mean 170 mAs, 120 kV) was acquired. The field ofview for the acquired datasets from the two scanners was the same, but these measurements are disturbed by the presence of a 256 mm × 256 mm with 512 × 512 matrix, resulting in an identical in- catheter in the narrow lumen . In this study, we test- plane voxel size of 0.5 mm × 0.5 mm. All patients were scanned with sin- ed different approaches to defining the reference method gle-breath-hold technique in the cranio-caudal direction through the using CTA alone or combined with functional methods, kidneys. Images were transferred over the network to a PACS system and also using varying thresholds for measured quantities (SECTRA, IDS5, Linköping, Sweden).
such as PSV and diameter reduction.
MRI examination was carried out on a 1.5 T scanner (Philips To evaluate and compare the four non-invasive techni- Achieva, Philips Healthcare, Best, the Netherlands) with an effective gra- ques used to diagnose RAS, we therefore recruited 47 dient strength of 114 mT/m, using a SENSE Body coil. The protocol in- non-diabetic patients with moderately reduced kidney func- cluded axial steady-state free precession (Balanced Turbo Field Echo) tion and clinical suspicion of RAS. The studied diagnostic images as well as coronal 3D gradient echo (Fast Field Echo) images(TE = 1.54 ms, TR = 5.4 ms, three dynamic phases, voxel size 0.7 × methods were CTA, MRA, renography and contrast- 0.7 × 1.0 mm3, covering the abdominal aorta and renal arteries), after in- enhanced ultrasound. Our main aim was to evaluate fea- jection of gadodiamide (Omniscan®, GE Healthcare, Oslo, Norway) or sibility and usability of these techniques and to make an Gd-DTPA (Magnevist®, Schering AG, Berlin, Germany) in a dose of FOR PERSONAL USE ONLY evaluation of their relationship to one another.
30 mL in a rate of 2.5 mL/s followed by 25 mL saline. In accordance withthe initial protocol, gadodiamide was used in 34 patients, but after thepublication of several reports concerning the association between nephro-genic systemic fibrosis and certain gadolinium agents [it was decided Materials and methods (in January 2007) to continue the study using Gd-DTPA (given in 13 pa-tients) restricted to patients with glomerular filtration rate >30 mL/min/ 1.73 m2. Synchronization between injection and acquisition was achieved Forty-seven patients of both genders, 18–80 years of age, with a screening with real-time imaging of the abdominal aorta during the injection.
serum creatinine 150–300 μmol/L living in the catchment area of Linköp-ing University Hospital in southeastern Sweden were consecutively re- Morphological image assessment.
Images from CT were reviewed as cruited for the study. Eligible patients had to have a resting blood original slices as well as with multiplanar reformat (MPR) and volume pressure >160 systolic and/or >90 mmHg diastolic or treatment with an- rendering technique (VRT) by one observer blinded for the other modal- tihypertensive medication, and suspicion of renovascular hypertension de- ities. Images from MRI were viewed as original slices, MPR and with fined as at least one of the following: (i) general atherosclerotic disease in maximum intensity projection (MIP) by a different observer blinded for coronary arteries, cerebrovascular or peripheral arterial disease according the other modalities. Analyses included an assessment of the main renal to patient file reviews, (ii) hypertension that developed or worsened sud- arteries and of the accessory arteries. With access to the original slices and denly, (iii) poorly controlled hypertension (>160/90 mmHg) despite use of MPR reformats, as well as digital measurement tools, the observers made three antihypertensive agents [(iv) malignant hypertension with reti- a decision on the presence of morphological stenosis exceeding 50% di- nopathy, fundus grade III or IV, and (v) increase in serum creatinine ameter reduction (in any direction) on a five-grade scale: 1 = definitely >20 μmol/L induced by angiotensin-converting enzyme (ACE) inhibitors absent, 2 = probably absent, 3 = inconclusive, 4 = probably present and or angiotensin II receptor antagonists ]. Exclusion criteria included di- 5 = definitely present. In comparison with other methods, 1–2 were con- Diagnosing renal artery stenosis in renal insufficiency sidered negative findings and 4–5 positive findings. The degree of steno- cated a diameter reduction exceeding 50% and at least one of the two sis was estimated on a six-grade scale: normal, diameter reduction >10% functional methods ultrasound and captopril renography supplemented but ≤30%, diameter reduction >30% but ≤50%, diameter reduction >50% by renin analysis indicated the presence of significant stenosis, then ‘mor- but ≤70%, diameter reduction >70%, and occlusion.
phological and functional stenosis' was considered to be positive.
Ultrasound was not part of the original protocol but was added later and carried out, according to a standardized protocol, in 36 patients. The ultrasound examinations were performed using a Siemens Descriptive statistics are given as mean ± standard deviation (SD) and ACUSON Sequoia C512 with a 4C2 probe (Siemens Medical Systems, number (percent), respectively. Confidence limits for sensitivity and spec- Forcheim, Germany) with pulsed wave Doppler at 2 MHz, imaging at ificity were obtained by exact calculation from the binomial distribution.
2–4 MHz, and high pulse repetition frequency mode, using a flank ap- The agreement between ultrasound and renography, as well as between proach and an intravenous contrast agent. The number of examiners in- CTA and MRA with respect to degree of stenosis, was evaluated as per- volved in the study was limited to two, and they were blinded to other cent agreement and with the (linearly weighted) kappa coefficient (with 95% confidence interval) [ The contrast agent Sonovue (Bracco Imaging SpA, Milan, Italy) was given as a 2.4-mL bolus dose or as a dose of 2.4 mL mixed with 10 mL ofsaline (NaCl 0.9%), producing ∼12.4 mL of contrast mixture, which wasinfused at a rate of 2 mL/min using a syringe pump (Bracco VueJect BR- INF 100). Contrast administration was repeated when deemed necessary.
During the exam, colour Doppler imaging was used to identify the re- nal arteries, and pulsed wave Doppler to measure the blood flow velocity.
Clinical background variables are summarized in , Measurements were made in the proximal, intermediate and distal renal and results of standard laboratory tests in The lab- artery. Post-examination evaluation was performed on the Siemens ACU- oratory tests confirmed that the patients had moderate re- SON KinetDx workstation.
nal failure. All patients included in the study were treated The diagnosis was based on the PSV ]. A positive finding was de- fined as a PSV value of at least 1.8 m/s ]. In those cases where no with antihypertensive drugs.
reliable velocity measurement was obtained, the examination was consid- The diagnostic procedures were carried out without ered inconclusive. The frequency of positive findings was also calculated complications. In none of the patients was there a rise in with an alternative PSV threshold of 2.5 m/s.
plasma creatinine by >12 μmol/L; in fact, there was a meandecrease of 13 μmol/L. No patient showed signs of nephro- Renography was exclusively performed as ACE genic systemic fibrosis at follow-up. Two patients declined inhibition renography ] including a 2-day protocol with a baseline re-nogram Day 1 and a captopril-stimulated renogram the following day.
MRI examination due to claustrophobia. The test material ACE inhibitors and angiotensin II-blockers were discontinued 7 days be- for the captopril test was lost in three cases. There was a fore the baseline examination.
blood pressure drop before the renin blood sample in one One hour before the renographic study Day 2, the patient received patient, most likely causing a false-positive captopril test.
25 mg of captopril (Capoten®, Bristol-Myers Squibb AB) orally. For reninanalysis, blood samples were collected after a 60-min rest with the patient Accessory arteries were seen with CTA and MRA in 16 in supine position before and 1 h after the administration of captopril. The patients (11 had 3 arteries, 4 had 4 arteries and one had 5 analytical method used measures the concentration of active renin by an arteries), whereas 31 patients (66%) had one artery to each immunoradiometric assay (IRMA Cisbio Bioassays). Reference values are 3–20 ng/L.
A dual-head large field of view gamma camera (GE XRT, Entegra, GE Medical, Milwaukee, WI, USA), equipped with a general-purpose paral- Table 1. Clinical characteristics of the 47 patients at inclusion lel-hole collimator, was used, and images were collected in a 128 × 128matrix. Starting immediately after the intravenous injection of 70 MBq99mTc-MAG3 (Mallinckrodt Ltd.), serial 10 s per frame images were ob- Mean ± SD or n (%) tained for 16–20 min.
Subsequent analysis was made using in-house software for renal scin- tigraphy, including calculation of relative renal function as well as abso- lute function (camera-based MAG3 clearance in millilitre per minute) Systolic BP, Day 1 (mmHg) Diastolic BP, Day 1 (mmHg) FOR PERSONAL USE ONLY The interpretation of the ACE inhibitor renography was based on the Number of antihypertensive drugs, criteria in ]. In cases of an intermediate test result, the final interpre- 1 week before study tation was resolved by adding the result of the renin analysis. A positive Treatment with ACE or AII inhibitors result was defined as an absolute P-renin level after stimulation exceeding (except the week immediately 50 ng/L and at least twice the basal level. Two of a total of six interme- diate renography results were thus turned into positive, and four into neg- Atherosclerotic heart disease ative tests.
Cerebrovascular disease Atherosclerotic limb disease The study was approved by the Regional Ethics Committee of Linköping and performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participating subjects.
Lipid-lowering therapy Inclusion criterion ‘rising plasma creatinine on ACE or AII inhibition' Methodological standards Inclusion criterion ‘at least 3 antihypertensive Using CTA-demonstrated stenosis reducing the vessel diameter by >50% Inclusion criterion ‘known atherosclerotic as the reference method, sensitivity and specificity of each diagnostic method were calculated. In addition, a combined criterion representing Inclusion criterion ‘sudden onset of or morphological as well as functional evidence of renal artery stenosis worsening of hypertension' was defined in the following way: if at least one of CTA and MRA indi- P. Eriksson et al.
Table 2. Laboratory values Day 1 and Day 2 Agreement between methods When the degree of stenosis in individual arteries wascompared between CTA and MRA, the agreement was Blood haemoglobin, Day 1 (g/L) moderate with no tendency to systematic over- or underes- Plasma hsCRP, Day 1 (mg/L) timation with MRA relative to CTA If only the Plasma creatinine, Day 1 (μmol/L) presence or absence of stenosis exceeding 50% diameter Plasma creatinine, Day 2 (μmol/L) reduction was considered, the observed agreement was Plasma urea, Day 1 (mmol/L) Plasma urea, Day 2 (mmol/L) 52.8% and kappa 0.576 (0.419–0.734).
Iohexol clearance (mL/min/1.73 m2 body area) When ultrasound was related to renography, both meth- Plasma triglycerides, fasting, Day 2 (mmol/L) ods agreed on a positive finding in 12 patients and on a Plasma cholesterol, fasting, Day 2 (mmol/L) negative finding in 13 patients. A positive ultrasound find- Plasma HDL cholesterol, fasting, Day 2 (mmol/L) ing was combined with a negative renography finding in Plasma LDL cholesterol, fasting, Day 2 (mmol/L) Plasma LDL/HDL ratio seven patients, and the converse in one patient [observed Fasting plasma glucose, Day 2 (mmol/L) agreement 75.8%; kappa = 0.530 (0.247–0.814)]. Whenevaluated separately for each kidney, concordant positivefindings were obtained for 6 kidneys, concordant negative Frequency of pathological findings findings for 32 kidneys, and discordant findings for 14kidneys, 6 of which with negative ultrasound and positive When the data were analysed at the individual level, so that renography result. In 20 cases, either method was incon- presence of arterial stenosis was defined for each patient, clusive. The observed agreement was 73.1% and kappa the frequency ranged between 30% for captopril renogra- 0.284 (0–0.604).
phy and 70% for CTA with stenosis defined as 50% diam-eter reduction When defined as 70% diameter reduction, the frequency of stenosis with CTA and MRA Evaluation using CTA as reference standard decreased, approaching the number of positive findings CTA-verified stenosis with >50% diameter reduction was obtained with renography.
present in 52 renal arteries, representing 50 kidneys in 33 When each kidney was evaluated separately, the fre- patients. Using this criterion as the reference method quency figures were consistently lower, ranging between the highest sensitivity was found for MRA, both 15% for captopril renography and 53% for CTA (with at patient and kidney level. However, at the patient level, 50% diameter reduction). When defined at the artery level, the sensitivity of ultrasound was only slightly lower. When the prevalence as detected by CTA and MRA became even evaluated for each kidney, captopril renography had con- siderably lower sensitivity values. The highest specificity, Table 3. Frequency of pathological findings with different diagnostic methods Evaluated at patient level (n = 47)CTA (>50% diameter reduction) CTA (>70% diameter reduction) MRA (>50% diameter reduction) MRA (>70% diameter reduction) Ultrasound (PSV ≥1.8 m/s) FOR PERSONAL USE ONLY Ultrasound (PSV ≥2.5 m/s) Captopril renography Captopril renography + renin analysis Evaluated at kidney level (n = 94)CTA (>50% diameter reduction) CTA (>70% diameter reduction) MRA (>50% diameter reduction) MRA (>70% diameter reduction) Ultrasound (PSV ≥1.8 m/s) Ultrasound (PSV ≥2.5 m/s) Captopril renography Captopril renography + renin analysis Evaluated at artery level (n = 116)CTA (>50% diameter reduction) CTA (>70% diameter reduction) MRA (>50% diameter reduction) MRA (>70% diameter reduction) aIncluding inconclusive findings in 14 kidneys contralateral to a kidney with positive finding.
Diagnosing renal artery stenosis in renal insufficiency Table 4. Degree of stenosis in individual arteries with CTA and MRA Diameter reduction by CTA Diameter reduction by MRA Agreement = 49.1% (54/110); linearly weighted kappa = 0.497 (0.386–0.608); McNemar: P = 1.000.
on the other hand, was found for captopril renography ing 50% diameter reduction but inconclusive functional when evaluated at the patient level, whereas comparable data. These 22 patients had uncontrolled hypertension specificity figures were found for all the tested methods and/or threat to substantial parts of the renal parenchyma at the kidney level.
as well as renal stenosis qualifying for dilatation, and all ofthem underwent PTRA.
Evaluation using the combined reference standard Summarizing the diagnostic findings to the combined cri- terion ‘morphological and functional stenosis' resulted in a positive diagnosis in 21 patients, a negative diagnosis in 13patients and inconclusive results in 13 patients. Relating As our findings show, all studied methods for diagnosis of each diagnostic method to this reference variable renal artery stenosis may be used in patients with moder- the highest sensitivity was found for CTA, and the highest ately impaired renal function. This is of particular interest specificity for ultrasound and captopril renography, regard- as most previous studies have not comprised this group of less of whether the analysis was carried out at the patient, patients. Also, ultrasound contrast agents do not seem to kidney or artery level. Raising the stenosis threshold for have been frequently used in earlier studies.
CTA and MRA to 70% diameter reduction resulted in The absence of an undisputable ‘gold standard' is prob- markedly lower sensitivity values, in particular for MRA.
lematic; although invasive angiography has a strong tradi- Captopril renography had lower sensitivity than ultrasound.
tion as a reference method, it relies only on morphologicinformation obtained from one or a few projections, thusignoring much of the spatial information in CTA andMRA as well as the functional information from Doppler Post-study arterial angiography and renal artery ultrasound and renography. Ideally, methods for diagnosing renal artery stenosis should be evaluated against the out- Although not a part of the study, catheter arteriography come of interventions such as PTRA. In clinical routine, was eventually performed in 17 patients with a positive di- however, the decision to undertake such an intervention agnosis according to the combined reference method and in a patient with renal failure is not based on a single diag- in 5 patients with CTA and MRA-verified stenosis exceed- nostic procedure, and evaluating its effect is confounded by FOR PERSONAL USE ONLY Table 5. Sensitivity and specificity of diagnostic methods relative to the presence of diameter reduction exceeding 50% according to CTA (95% confidence interval) (95% confidence interval) Evaluated at patient level (n = 47)MRA (>50% diameter reduction) 0.806 (0.625–0.925) 0.786 (0.492–0.953) Ultrasound (PSV ≥1.8 m/s) 0.704 (0.498–0.862) 0.889 (0.518–0.997) Captopril renography + renin analysis 0.424 (0.255–0.608) 1.000 (0.807–1.000) Evaluated at kidney level (n = 94)MRA (>50% diameter reduction) 0.756 (0.597–0.876) 0.816 (0.680–0.912) Ultrasound (PSV ≥1.8 m/s) 0.528 (0.355–0.696) 0.806 (0.640–0.918) Captopril renography + renin analysis 0.295 (0.168–0.452) 0.860 (0.733–0.942) Evaluated at artery level (n = 116)MRA (>50% diameter reduction) 0.674 (0.515–0.809) 0.794 (0.679–0.883) TP, true positive; FP, false positive; TN, true negative; FN, false negative.
P. Eriksson et al.
Table 6. Sensitivity and specificity of diagnostic methods relative to the provisional reference method ‘functional and morphological stenosis' withPSV threshold 1.8 m/s (95% confidence interval) (95% confidence interval) Evaluated at patient level (n = 34; reference method missing in 13 cases)CTA (>50% diameter reduction) 1.000 (0.867–1.000) 0.615 (0.316–0.861) CTA (>70% diameter reduction) 0.810 (0.581–0.946) 1.000 (0.794–1.000) MRA (>50% diameter reduction) 0.900 (0.683–0.988) 0.692 (0.386–0.909) MRA (>70% diameter reduction) 0.600 (0.361–0.809) 0.846 (0.546–0.981) Ultrasound (PSV ≥1.8 m/s) 0.905 (0.696–0.988) 1.000 (0.794–1.000) Captopril renography + renin analysis 0.667 (0.430–0.854) 1.000 (0.794–1.000) Evaluated at kidney level (n = 61; reference method missing in 33 cases)CTA (>50% diameter reduction) 0.964 (0.817–0.999) 0.758 (0.577–0.889) CTA (>70% diameter reduction) 0.643 (0.441–0.814) 0.939 (0.798–0.993) MRA (>50% diameter reduction) 0.852 (0.663–0.958) 0.788 (0.611–0.910) MRA (>70% diameter reduction) 0.444 (0.255–0.647) 0.909 (0.757–0.981) Ultrasound (PSV ≥1.8 m/s) 0.714 (0.513–0.868) 0.970 (0.842–0.999) Captopril renography + renin analysis 0.500 (0.306–0.694) 0.970 (0.842–0.999) Evaluated at artery level (n = 74; reference method missing in 42 cases)CTA (>50% diameter reduction) 0.935 (0.786–0.992) 0.791 (0.640–0.900) CTA (>70% diameter reduction) 0.581 (0.391–0.755) 0.953 (0.842–0.994) MRA (>50% diameter reduction) 0.733 (0.541–0.877) 0.786 (0.632–0.897) MRA (>70% diameter reduction) 0.400 (0.227–0.594) 0.929 (0.805–0.985) TP, true positive; FP, false positive; TN, true negative; FN, false negative.
the effects of concurrent medical therapy, patient-related of positive cases from 70% to 62%. The high sensitivity of preferences, and costs. We therefore judged it impractical CTA against this standard comes as no surprise, but its re- to use therapeutic outcome as a reference method in this markably low specificity raises the suspicion that CTA may group of patients.
identify morphological stenoses even in the absence of sub- An alternative might be to base the reference diagnosis stantial effects on the blood flow through the vessel. The on invasive measurement of the pressure drop across the specificity of ultrasound and captopril renography was, in stenosis In a semi-experimental study, the pressure general, higher than that of the morphological methods, un- drop was shown to be related to the release of renin behind less the stenosis thresholds were raised to 70%. The sensi- the stenosed artery ]. The obvious drawback is that this tivity for ultrasound was higher than that for captopril diagnostic procedure requires the introduction of a catheter renography. A related issue, not addressed in this study, is for pressure measurements into the arterial system of the whether the functional information present in ultrasound patient, with known complication risks. Hence, we consid- and captopril renography can be replaced by quantitative ered it ethically unacceptable to carry out catheterization in MRI phase-contrast velocity measurements ]. Re- those of our patients where non-invasive diagnostic meth- gardless of which method is used for functional assessment, ods did not indicate any stenosis. Furthermore, the presence it seems that combining morphological and functional data of the catheter itself may influence the pressure measure- in a strictly defined variable might be useful in future stud- FOR PERSONAL USE ONLY ments It may also be difficult to apply and inter- ies of renal artery stenoses.
pret pressure measurements to tandem stenoses.
In general, the frequency of renal artery stenosis was Considering these difficulties in establishing a suitable higher than what we had expected in this population. The reference method, we decided to use CTA, the morpholog- large differences in frequency of pathological findings be- ical technique offering the highest spatial resolution, as our tween methods revealed are remarkable. The primary reference method. We then found MRA to have su- findings also illustrate the fact that prevalence figures re- perior sensitivity compared to ultrasound and captopril re- ferring to subjects must not be compared with figures re- nography, regardless of whether patients, kidneys or arteries ferring to separate kidneys or individual arteries. The were considered. MRA is also the only one of the studied prevalence of renovascular hypertension in the general hy- methods, in addition to CTA, that can reliably distinguish pertensive population has been reported to be <1%, but as between several arteries supplying the same kidney. Speci- high as 20–40% in highly selected materials [One ficity, on the other hand, was higher for captopril renogra- might consider whether the low frequency of positive re- phy and Doppler ultrasound at the patient level. At the nography findings could reflect the frequency of critical kidney level, all three methods had comparable specificity.
stenosis more appropriate than stenosis defined by 50% di- The alternative criterion, ‘functional and morphological ameter reduction at CTA. Studying this problem is difficult stenosis' was an attempt to include functional as without recourse to selective catheterization methods.
well as morphological information in the reference method.
In our material, the agreement between the two mor- The effect was only a moderate reduction of the proportion phological methods, CTA and MRA, was moderate, and Diagnosing renal artery stenosis in renal insufficiency a limited agreement between ultrasound and captopril re- 6. Taylor A, Villines T, Stanek E et al. Extended-release niacin or eze- nography at the kidney level was also found. Renography timibe and carotid intima-media thickness. N Engl J Med 2009; 361: is a method for detecting renovascular hypertension and 7. Grobbee DE, Bots ML. Atherosclerotic disease regression with sta- not primarily RAS. The method is based on activation of tins: studies using vascular markers. Int J Cardiol 2004; 96: 447–459 the renin–angiotensin–aldosterone system in the affected 8. Fleg JL, Mete M, Howard BV et al. Effect of statins alone versus kidney, due to a substantial reduction in post-stenotic per- statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: fusion pressure and a suppression of contralateral renin the SANDS (Stop Atherosclerosis in Native Diabetic Study) trial.
secretion [The fact that captopril renography cannot J Am Coll Cardiol 2008; 52: 2198–2205 give useful information on the contralateral side in positive 9. Takayama T, Hiro T, Yamagishi M et al. Effect of rosuvastatin on coronary atheroma in stable coronary artery disease: multicenter cor- cases is reflected in the present study as lower sensitivity onary atherosclerosis study measuring effects of rosuvastatin using and specificity at the kidney level, as all contralateral find- intravascular ultrasound in Japanese subjects (COSMOS). Circ J ings have been defined as inconclusive.
2009; 73: 2110–2117 For the clinical situation, it should be specified whether 10. Taylor A, Nally J, Aurell M et al. Radionuclides in Nephrourology we want a method with high specificity for selection of pa- Group. Consensus Group on ACEI Renography. Consensus report on tients suitable for PTRA or a method with high sensitivity ACE inhibitor renography for detecting renovascular hypertension.
suitable for screening of renovascular disease (ischaemic J Nucl Med 1996; 37: 1876–1882 11. Desberg AL, Paushter DM, Lammert GK et al. Renal artery stenosis: nephropathy). Only identifying severe stenosis may be in- evaluation with color Doppler flow imaging. Radiology 1990; 177: sufficient if we want to treat renovascular disease aggres- sively with antihypertensive and lipid-lowering therapy, a 12. Williams GJ, Macaskill P, Chan SF et al. Comparative accuracy of strategy that recently has been shown to decrease intima- renal duplex sonographic parameters in the diagnosis of renal artery media thickness in atherosclerosis . Potential risks of stenosis: paired and unpaired analysis. AJR Am J Roentgenol 2007; the diagnostic methods used here mainly relate to the in- 13. Wei K, Le E, Bin JP et al. Quantification of renal blood flow with con- jected contrast media, as the radiation dose is a minor con- trast-enhanced ultrasound. J Am Coll Cardiol 2001; 37: 1135–1140 cern in the current age group. Both iodine (for CTA) and 14. Rubin GD, Walker PJ, Dake MD et al. Three-dimensional spiral com- gadolinium (for MRA) are problematic in this type of pa- puted tomographic angiography: an alternative imaging modality for tients . However, we observed no cases of either the abdominal aorta and its branches. J Vasc Surg 1993; 18: 656–664 contrast-induced nephropathy or nephrogenic systemic fi- 15. Prince MR, Narasimham DL, Stanley JC et al. Breath-hold gadolin- brosis in our limited group of patients. The ultrasound pro- ium-enhanced MR angiography of the abdominal aorta and its majorbranches. Radiology 1995; 197: 785–792 tocol we have used included the use of a contrast agent 16. Killen DA, Oh SU. Quantitation of the severity of arterial stenosis by with a very good safety profile ].
pressure gradient measurement. Am Surg 1968; 34: 341–349 In conclusion, in our material consisting of hypertensive 17. Nahman NS, Maniam P, Hernandez RA et al. Renal artery pressure non-diabetic patients with moderate renal insufficiency, gradients in patients with angiographic evidence of atherosclerotic CTA and MRA both seem apt to diagnose stenosis in renal artery stenosis. Am J Kidney Dis 1994; 24: 695–699 the renal artery with a diameter reduction of 50% or more, 18. Gross CM, Kramer J, Weingartner O et al. Determination of renal whereas ultrasound and, in particular, renography were less arterial stenosis severity: comparison of pressure gradient and vesseldiameter. Radiology 2001; 220: 751–756 sensitive in this respect. In the clinical workflow, however, 19. Eklöf H, Ahlström H, Boström A et al. Renal artery stenosis evalu- ultrasound and renography may have complementary ated with 3D-Gd-magnetic resonance angiography using transstenotic roles, where the high-sensitivity ultrasound method may pressure gradient as the standard of reference. A multireader study.
be useful in screening before morphological stenosis has Acta Radiol 2005; 46: 802–809 been diagnosed and the more restrictive captopril renogra- 20. Colyer WR Jr, Cooper CJ, Burket MW et al. Utility of a 0.014" pres- phy by confirming the effect on renin secretion of a mor- sure-sensing guidewire to assess renal artery translesional systolicpressure gradients. Catheter Cardiovasc Interv 2003; 59: 372–377 phological stenosis whose haemodynamic consequences 21. Pettersson H. Hydro- and hemodynamic effects of catheterization of are otherwise unclear.
FOR PERSONAL USE ONLY vessels. Lund 1976; Doctoral dissertation 22. Serruys PW, Wijns W, Reiber JH et al. Values and limitations of This study was supported by the regional Research transstenotic pressure gradients measured during percutaneous coro- Council of Southeast Sweden (FORSS).
nary angioplasty. Herz 1985; 10: 337–342 23. Dash RK, Jayaraman G, Mehta KN. Flow in a catheterized curved Conflict of interest statement. None declared.
artery with stenosis. J Biomech 1999; 32: 49–61 24. Fearon WF. Physiologic assessment of renal artery stenosis: will his- tory repeat itself? J Am Coll Cardiol 2006; 48: 1856–1858 25. Myers D, Poole L, Imam K et al. Renal artery stenosis by three- dimensional magnetic resonance angiography in type 2 diabetes with 1. Wheatley K, Ives N, Gray R et al. Revascularization versus medical uncontrolled hypertension and chronic renal insufficiency: preva- therapy for renal-artery stenosis. N Engl J Med 2009; 12: 1953–1962 lence and effect of renal function. Am J Kidney Dis 2003; 41: 2. Textor SC. Ischemic nephropathy: where are we now? J Am Soc Ne- phrol 2004; 15: 1974–1982 26. Krijnen P, van Jaarsveld B, Steyerberg E et al. A clinical prediction 3. Levin A, Linas S, Luft F et al. Controversies in renal artery stenosis: a rule for renal artery stenosis. Ann Intern Med 1998; 129: 705–711 review by the American Society of Nephrology Advisory Group on 27. Marckmann P, Skov L, Rossen K et al. Nephrogenic systemic fibrosis: hypertension. Am J Nephrol 2007; 27: 212–220 suspected causative role of gadodiamide used for contrast-enhanced 4. Caps M, Zierler RE, Polissar N et al. Risk of atrophy in kidneys with magnetic resonance imaging. J Am Soc Nephrol 2006; 17: 2359–2362 atherosclerotic renal artery stenosis. Kidney Int 1998; 53: 735–742 28. Hansen KJ, Edwards MS, Craven TE. Prevalence of renovascular dis- 5. Zucchelli P, Zuccalà A. Can we accurately diagnose nephrosclerosis? ease in the elderly: a population-based study. J Vasc Surg 2002; 36: Nephrol Dial Transplant 1995; 10: 2–5 P. Eriksson et al.
29. Granerus G, Moonen M. Effects of extra-renal background subtrac- netic resonance blood flow data. J Magn Reson Imaging 2008; 27: tion and kidney depth correction in the measurement of GFR by gam- ma camera renography. Nucl Med Commun 1991; 12: 519–527 35. Chrysochou C, Kalra PA. Epidemiology and natural history of athero- 30. Cohen J. Weighted kappa: nominal scale agreement with provision sclerotic renovascular disease. Prog Cardiovasc Dis 2009; 52: 184–195 for scaled disagreement or partial credit. Psychol Bull 1968; 70: 36. Vaughan ED, Buhler FR, Laragh JH et al. Renovascular hyperten- sion: renin measurements to indicate hypersecretion and contralateral 31. De Bruyne B, Manoharan G, Pijls NH et al. Assessment of renal ar- suppression, estimate renal plasma flow, and score for surgical cur- tery stenosis severity by pressure gradient measurements. J Am Coll ability. Am J Med 1973; 55: 402–414 Cardiol 2006; 7: 1851–1855 37. Prince MR, Arnoldus C, Frisoli JK. Nephrotoxicity of high-dose gad- 32. Cortsen M, Petersen LJ, Ståhlberg F et al. MR velocity mapping mea- olinium compared with iodinated contrast. J Magn Reson Imaging surement of renal artery blood flow in patients with impaired kidney 1996; 6: 162–166 function. Acta Radiol 1996; 37: 79–84 38. Bokor D, Chambers JB, Rees PJ et al. Clinical safety of SonoVue, a 33. Schoenberg SO, Knopp MV, Bock M et al. Renal artery stenosis: new contrast agent for ultrasound imaging, in healthy volunteers and grading of hemodynamic changes with cine phase-contrast MR blood in patients with chronic obstructive pulmonary disease. Invest Radiol flow measurements. Radiology 1997; 203: 45–53 2001; 36: 104–109 34. Larsson M, Persson A, Eriksson P et al. Renal artery stenosis: extract- ing quantitative parameters with a mathematical model fitted to mag- Received for publication: 11.2.10; Accepted in revised form: 20.4.10 FOR PERSONAL USE ONLY
CLINICAL ASPECTS OF SALIVARY BIOLOGY FORTHE DENTAL CLINICIAN LAURENCE J. WALSH stimulated salivary flow rate to the prevention of dental caries Saliva performs a multiplicity of roles within the oral cavity, and dental erosion can be also explained by improved clearance and like many things in life, its importance is usually not of substrate due to more rapid movement of the salivary film,