Assessment of renal fibrosis and anti-fibrotic agents using a novel diagnostic and stain-free second-harmonic generation platform.

Current histological measurement techniques for interstitial collagen, the basis of interstitial fibrosis, are semi-quantitative at best and only provide a ratio of collagen levels within tissues. The Genesis200 imaging system and supplemental image analysis software, FibroIndex from HistoIndex, is a novel, automated platform that uses second-harmonic generation (SHG) for imaging and characterization of interstitial collagen deposition and additional characteristics, in the absence of any staining. However, its ability to quantify renal fibrosis requires investigation. This study compared SHG imaging of renal fibrosis in mice with unilateral ureteric obstruction (UUO), to that of Masson's trichrome staining (MTS) and immunohistochemistry (IHC) of collagen I. Additionally, the platform generated data on collagen morphology and distribution patterns. While all three methods determined that UUO-injured mice underwent significantly increased renal fibrosis after 7 days, the HistoIndex platform additionally determined that UUO-injured mice had a significantly increased collagen-to-tissue cross reticulation ratio (all P < .001 vs sham group). Furthermore, in UUO-injured mice treated with the relaxin family peptide receptor-1 agonists, relaxin (0.5 mg/kg/day) or B7-33 (0.25 mg/kg/day), or angiotensin converting enzyme-inhibitor, perindopril (1 mg/kg/day) over the 7-day period, only the HistoIndex platform determined that the drug-induced prevention of renal fibrosis correlated with significantly reduced collagen fiber thickness and collagen-to-tissue cross reticulation ratio, but increased collagen fiber counts. Relaxin or B7-33 treatment also increased renal matrix metalloproteinase-2 and reduced tissue inhibitor of metalloproteinase-1 levels (all P < .01 vs UUO alone). This study demonstrated the diagnostic value of the HistoIndex platform over currently used staining techniques.

Assessment of renal fibrosis in a rat model of unilateral ureteral obstruction with diffusion kurtosis imaging: Comparison with α-SMA expression and 18F-FDG PET.

PURPOSE: To investigate the utility of diffusion kurtosis imaging (DKI) MRI for evaluation of renal fibrosis in rats with unilateral ureteral obstruction (UUO). METHODS: Twenty-five rats had UUO, and ten rats were subjected to sham operation as control. DKI was performed on a 3.0 T MRI scanner on days 1, 3, 5, and 7 after ligation. All rats then underwent 18F-FDG dynamic PET to evaluate unilateral renal function, followed by histological analysis to examine α-smooth muscle actin (α-SMA) expression. DKI metrics were assessed among the time points and between two sides, and compared with maximum standardized uptake value (SUVmax), serum levels of creatinine and urea, and fibrosis marker α-SMA. RESULTS: Mean kurtosis (MK) on day 7, axial kurtosis (Ka) on days 3 and 7, mean diffusivity (MD) on days 1, 3, 5, and 7, and fractional anisotropy (FA) on days 3, 5, and 7 of cortex and medulla between the UUO and contralateral sides were significantly different (all p < 0.05). Over the course of UUO progression, there were significant changes in Ka, MD and FA of medulla (all p < 0.05). FA of medulla was positively correlated with SUVmax (r = 0.641, p < 0.001), and MD of cortex was negatively correlated with urea (r = -0.534, p = 0.001). MD of cortex was negatively correlated with α-SMA on UUO sides (r = -0.710, p < 0.001). CONCLUSIONS: DKI shows the potential for noninvasive assessment of renal fibrosis and unilateral renal function induced by UUO.

Hydronephrosis severity score: an objective assessment of hydronephrosis severity in children-a preliminary report.

The main challenge in the management of antenatally diagnosed hydronephrosis and ureteropelvic junction obstruction (UPJO) is to differentiate the one that is likely to resolve from the pathological one. In this study, a new hydronephrosis severity score (HSS), combining ultrasonographic and renographic parameters, has been developed. Hydronephrosis severity score was analyzed with regard to its usefulness in assessing the severity of UPJO, postoperative resolution, and interobserver reliability. METHODS: Hydronephrosis severity score was devised with three parameters: differential renal function (DRF), drainage curve pattern, and ultrasonogram grade (Table 1). Hydronephrosis severity score ranges were divided as 0-4, mild; 5-8, moderate; and 9-12, severe and compared with clinical outcomes (resolution, persistence, or surgical intervention) by retrospective case record review of children with unilateral UPJO. Among those who underwent surgery, surgical outcomes were compared with changes in HSS at 6-month follow-up. Hydronephrosis severity score was computed by three observers, and interobserver variability was calculated. RESULTS: A total of 125 case records (male:female = 93:32; right:left = 44:81) were analyzed. Among the patients analyzed, none (0/59) with HSS 0-4 warranted surgery, whereas 1 of 35 patients with HSS 5-8 underwent surgery, and all (31/31) with HSS 9-12 underwent surgery (P = 0.001). Overall, hydronephrosis resolved in 65, persisted in 28, and required surgery in 32 patients. Mean (standard deviation) HSS was 2.1 (0.75) in whom it resolved, 6.2 (0.78) in whom it persisted, and 10.2 (0.79) in those who underwent surgery (analysis of variance P = 0.001). Among those who underwent surgery, a better recovery of HSS was noted in younger infants (aged 2-5 months) with higher pre-operative DRF. There was 94.4% median agreement between radiologists and the surgeon (kappa 0.851), indicating a very good interobserver agreement. DISCUSSION: Loss of DRF on progressive renograms remains the accepted criterion of significant UPJO although the lost function does not always recover after pyeloplasty. Newer scoring systems keep evolving to predict the need for surgery as well as assess resolution of UPJO, and the study's preliminary report suggests that HSS could turn out to be one such useful tool. In this study, those who deteriorated were the ones with HSS ≥9. One can use this as a criterion and decide on intervention before DRF deterioration. Hydronephrosis severity score could also be applied as an objective parameter for quantifying improvement/deterioration after surgery and comparing outcomes across centers. The drawbacks of the present study are its small size and the retrospective nature. Further prospective studies are required to validate the usefulness of HSS.

Intravoxel incoherent motion MRI-derived parameters and T2* relaxation time for noninvasive assessment of renal fibrosis: An experimental study in a rabbit model of unilateral ureter obstruction.

PURPOSE: To evaluate the association of apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM) MRI-derived parameters, and T2* relaxation time with histopathological changes observed during renal fibrogenesis in a rabbit model of unilateral ureter obstruction (UUO). METHODS: Twenty New Zealand White rabbits underwent baseline MRI followed by surgery (sham or UUO) and then follow-up MRI at postoperative day (POD) 0, 3, 7, and 14. Hematoxylin and eosin and Masson's trichrome staining was performed to evaluate cell density and area of fibrosis. Spearman rank correlation and Pearson correlation tests and one-way analysis of variance were used for statistical analyses. RESULTS: There was a continuous increase in the area of fibrosis and cell density: rho = 0.900 (95% confidence interval [CI] = 0.760, 0.960; p < 0.0001) and 0.904 (95% CI = 0.769, 0.962; p < 0.0001), respectively. There was a tendency for all MRI variables to decrease at POD 3 and partly recover at POD 7. ADC, D, f, and T2* relaxation time showed significant correlation with area of fibrosis and cell density (r = -0.5177 and -0.6962, -0.5395 and -0.7851, -0.7168 and -0.7902, and -0.6808 and -0.7212, respectively; p = 0.0052-0.0481) while D* did not (p = 0.1997 and 0.7853, respectively). CONCLUSIONS: ADC, IVIM MRI-derived parameters, and T2* relaxation time were significantly associated with the area of fibrosis and cell density during renal fibrogenesis in a rabbit model of UUO. After validation in future studies, MRI may have potential for noninvasive assessment modality of renal fibrosis.

Stenting for malignant ureteral obstruction: Tandem, metal or metal-mesh stents.

Extrinsic malignant compression of the ureter is not uncommon, often refractory to decompression with conventional polymeric ureteral stents, and frequently associated with limited survival. Alternative options for decompression include tandem ureteral stents, metallic stents and metal-mesh stents, though the preferred method remains controversial. We reviewed and updated our outcomes with tandem ureteral stents for malignant ureteral obstruction, and carried out a PubMed search using the terms "malignant ureteral obstruction," "tandem ureteral stents," "ipsilateral ureteral stents," "metal ureteral stent," "resonance stent," "silhouette stent" and "metal mesh stent." A comprehensive review of the literature and summary of outcomes is provided. The majority of studies encountered were retrospective with small sample sizes. The evidence is most robust for metal stents, whereas only limited data exists for tandem or metal-mesh stents. Metal and metal-mesh stents are considerably more expensive than tandem stenting, but the potential for less frequent stent exchanges makes them possibly cost-effective over time. Urinary tract infections have been associated with all stent types. A wide range of failure rates has been published for all types of stents, limiting direct comparison. Metal and metal-mesh stents show a high incidence of stent colic, migration and encrustation, whereas tandem stents appear to produce symptoms equivalent to single stents. Comparison is difficult given the limited evidence and heterogeneity of patients with malignant ureteral obstruction. It is clear that prospective, randomized studies are necessary to effectively scrutinize conventional, tandem, metallic ureteral and metal-mesh stents for their use in malignant ureteral obstruction.

Assessment of renal function in patients with unilateral ureteral obstruction using whole-organ perfusion imaging with 320-detector row computed tomography.

BACKGROUND: Obstructed nephropathy is a common complication of several disease processes. Accurate evaluation of the functional status of the obstructed kidney is important to achieve a good outcome. The purpose of this study was to investigate renal cortical and medullary perfusion changes associated with unilateral ureteral obstruction (UUO) using whole-organ perfusion imaging with 320-detector row computed tomography (CT). METHODOLOGY/PRINCIPLE FINDINGS: Sixty-four patients with UUO underwent whole-organ CT perfusion imaging. Patients were divided into 3 groups, mild, moderate, and severe, based on hydronephrosis severity. Twenty sex- and age-matched patients without renal disease, who referred to abdominal CT, were chosen as control subjects. Mean cortical and medullary perfusion parameters of obstructed and contralateral kidneys were compared, and mean perfusion ratios between obstructed and contralateral kidneys were calculated and compared. Mean cortical or medullary blood flow (BF) and blood volume (BV) of the obstructed kidneys in the moderate UUO and BF, BV, and clearance (CL) in the severe UUO were significantly lower than those of the contralateral kidneys (p < 0.05). The mean cortical or medullary BF of the obstructed kidney in the moderate UUO, and BF, BV, and CL in the severe UUO were significantly lower than those of the kidneys in control subjects (p < 0.05). Mean cortical or medullary BF of the non-obstructed kidneys in the severe UUO were statistically greater than that of normal kidneys in control subjects (p < 0.05). An inverse correlation was observed between cortical and medullary perfusion ratios and grades of hydronephosis (p < 0.01). CONCLUSIONS/SIGNIFICANCE: Perfusion measurements of the whole kidney can be obtained with 320-detector row CT, and estimated perfusion ratios have potential for quantitatively evaluating UUO renal injury grades.

[(99m)Tc-MAG3 diuretic renography in assessment of obstructive uropathy. The new test F+10SP: a step ahead in the differential diagnosis]. / Scintigrafia renale sequenziale con diuretico (99m)Tc-MAG3, nella valutazione della uropatia ostruttiva. La nuova procedura F+10SP: un passo avanti nella diagnosi differenziale.

BACKGROUND: Dilation of the renal pelvis is a problem Urologists have often to deal with. One of the key aspects is to clear if the dilation is the consequence of an obstruction to the outflow or a simple anatomic variant. Aim of this study was to compare two diuretic renographic procedures, F-15 vs the new procedure F+10SP (Seated Position) in a group of hydronephrotic patients, in order to increase the accuracy in the differential diagnosis between non-obstructive and obstructive dilation. MATERIALS AND METHODS: 34 Patients (14 male, 20 female, 18-71 yrs range), 27 pts having an unilateral hydronephrosis and 7 pts a bilateral hydronephrosis diagnosed by ultrasound, were enclosed in the study. They were subjected to two 99mTc-MAG3 diuretic renography with furosemide consecutively, with different modalities: 1) 40 mg of furosemide were administered IV to patient in supine position 15 minutes before tracer injection (Test F-15, by English); 2) the new procedure: 20 mg of furosemide were administered IV to patient in Seated Position (SP), 10 minutes after tracer injection during dynamic acquisition (Test F+10 SP). The average interval between the two tests was 7 days. Two different physicians analyzed all the tests. The results were classified as: non-obstruction (only F+10SP can distinguish between normal and dilated without obstruction), obstruction, equivocal and not applicable. RESULTS: Among the 68 renal units (RU) included in the analysis, the F+10SP test showed normal findings in 21 RU (30,8%), dilation without obstruction in 21 RU (30,8%), obstruction in 25 RU (36.8%) and equivocal result in 1 RU. The F-15 renography showed non-obstructive results in 35 RU (51.5%), obstruction in 20 RU (29.4%) and equivocal findings in 11 RU (16.1%); the test was not applicable in 2 RU (2.9%) due to insufficient renal function. Side effects reported for the F-15 renogram were hypotension in 1 patient, renal colic in 3 patients, bladder filling in 13 patients, disruption because of voiding in 4 patients. No complications were observed during or after the F+10SP renography. The 20 RU diagnosed with obstruction at the F-15 test were considered obstructed also at the F+10SP test. CONCLUSIONS: The "equivocal" test rate lowered from 16% for the F-15 test to less than 1.5% for the new F+10 SP test. The F+10SP procedure is easy, well tolerated, time saving and seems to be a more reliable tool in assessment of obstructive uropathy in adults.

Urologic assessment of decreasing renal function.

The discussion of renal failure as it relates to urology is largely a discussion of obstructive uropathy. Obstructive uropathy has been identified in multiple series to account for approximately 10% of all cases of renal failure. On a total population scale, autopsy series have shown the prevalence of hydronephrosis in 3% of men and women who are younger than 65 years and 6% of men older than 65 years. When benign prostatic hypertrophy and renal stone disease are considered, obstructive uropathy is also one of the most common indications for surgery. In this review, the different causes of obstructive renal insufficiency and management options available are discussed.

Direct primary or secondary percutaneous ureteral stenting: what is the most compliant option in patients with malignant ureteral obstructions?

The objective of this study was to analyze three ureteral stenting techniques in patients with malignant ureteral obstructions, considering the indications, techniques, procedural costs, and complications. In the period between June 2003 and June 2006, 45 patients with bilateral malignant ureteral obstructions were evaluated (24 males, 21 females; average age, 68.3; range, 42-87). All of the patients were treated with ureteral stenting: 30 (mild strictures) with direct stenting (insertion of the stent without predilation), 30 (moderate/severe strictures) with primary stenting (insertion of the stent after predilation in a one-stage procedure), and 30 (mild/moderate/severe strictures with infection) with secondary stenting (insertion of the stent after predilation and 2-3 days after nephrostomy). The incidence of complications and procedural costs were compared by a statistical analysis. The primary technical success rate was 98.89%. We did not observe any major complications. The minor complication rate was 11.1%. The incidence of complications for the various techniques was not statistically significantly. The statistical analysis of costs demonstrated that the average cost of secondary stenting (637 euros; SD, 115 euros) was significantly higher than that of procedures which involved direct or primary stenting (560 euros; SD, 108 euros). We conclude that one-step stenting (direct or primary) is a valid option to secondary stenting in correctly selected patients, owing to the fact that when the procedure is performed by expert interventional radiologists there are high technical success rates, low complication rates, and a reduction in costs.

Assessment of obstruction in adult ureterocele by means of color Doppler duplex sonography.

AIM: The purpose of this study is to present a method for identifying a ureteral obstruction in unilateral orthotopic ureterocele by means of conventional sonography and color Doppler duplex sonography. We focus on the measurement of the ureterocele dimensions, the degree of dilation it causes to the ipsilateral upper urinary tract, the registration of urine out-flow from the ureteral orifice into the bladder and its spectral analysis. MATERIAL AND METHOD: Over 2 years at our institutions, 8 adult patients (7 women, 1 man) were diagnosed as having a single system orthotopic ureterocele. Four of them presented with lumbar pain, dysuria and recurrent urinary tract infections, while the remainder were asymptomatic and diagnosed accidentally. The diagnosis was based on serial sonography of the upper and lower urinary tract confirmed by intravenous pyelography and cystoscopy. We also performed color Doppler duplex sonographic evaluation of the urine jets ejected from both ureteral orifices into the bladder. Using the flow spectral study we analyzed the waveforms and measured their duration and flow rate. The study was completed with a comparative analysis of the data obtained from both ureteral orifices. RESULTS: Cystic dilation of the lower ureteric extremity into the bladder was presented in all cases. Upper urinary tract dilation, of various grades, was present in 4 of 8 patients. Differences in urine jets between those derived from the ureterocele and those from the healthy contralateral ureteral orifice were significant in those patients with dilation of the upper urinary tract. The differences concerned mainly the frequency and symmetry of the jets as well as the pattern, duration and velocity of their waves. The 4 above-mentioned patients, with dilated upper urinary tracts and waveforms differentiated from the contralateral ones, were characterized as obstructive. On the other hand, the remaining 4 patients with subclinical ureterocele showed insignificant differences in urine jets and waveforms, and were found to be non-obstructive. CONCLUSION: Conventional sonography of the urinary tract in combination with color Doppler duplex sonography of the ureteral jets can be used in an attempt to diagnose and evaluate a unilateral orthotopic (single system) ureterocele and assess the necessity of intervention to identify the obstruction.

Fast imaging MR assessment of ureterohydronephrosis during pregnancy.

PURPOSE: to assess the value of the fast imaging sequence called RARE-MR-Urography (RMU) for the diagnosis of pathologic ureterohydronephrosis during pregnancy. MATERIALS AND METHODS: 15 pregnant women with an acute flank pain were examined with RMU. Results were compared with those of ultrasonography (US), X-rays, and the evolution of symptoms. RESULTS: the accuracy of RMU in the detection of urinary tract dilatation and the localization of the level of obstruction was excellent (100%). The determination of the type of obstruction, intrinsic vs. extrinsic, was always exact. RMU alone cannot specify the exact nature of the intrinsic obstruction. Ultrasonography gave less sensitive information in terms of level (60%) and type of obstruction (53%). CONCLUSION: RMU is able to differentiate a physiological from a pathologic ureterohydronephrosis during pregnancy. It could be considered as a procedure of choice for special cases when US failed to establish this differential diagnosis.

The assessment of obstruction in the newborn with unilateral hydronephrosis by measuring the size of the opposite kidney.

We measured the size of the normal kidney opposite a unilateral hydronephrotic kidney in infants to determine if compensatory changes occurred and could be used as a diagnostic test for defining or excluding obstruction. Comparison of subgroups of neonates with unilateral hydronephrosis or multicystic renal dysplasia to normal controls demonstrated that compensatory changes do occur in the normal kidney. Normal kidneys opposite obstructed hydronephrotic kidneys requiring surgery became larger than normal for age. Normal kidneys opposite nonobstructed poorly functioning hydronephrotic kidneys whose function rapidly improved were smaller than normal for age. These changes in renal growth by the normal newborn kidney reflect renal counterbalance, which is exaggerated in this age group and which may be used to corroborate rapid changes in renal function caused by the presence or absence of obstruction. By plotting serial measurements of normal renal length on a renal growth chart, the diagnosis of obstruction in newborn hydronephrosis can be facilitated and the clinical management of the patient improved.

Volume expanded diuretic renography in the postnatal assessment of suspected uretero-pelvic junction obstruction.

Controversy surrounds the role of 99mTc-diethylenetriamine pentaacetic acid renography in suspected uretero-pelvic junction obstruction in early life. Accordingly, we retrospectively reviewed 18 patients (28 hydronephrotic kidneys) with a mean age of 2 mo (range: 1 wk-6 mo) who underwent a total of 36 scans using intravenous volume expansion (10 ml/kg) and furosemide diuresis (1 mg/kg). Initial scans were classified as obstructed, not obstructed or indeterminate using differential renal function, furosemide washout T 1/2 and visual assessment of tracer clearance. Those initially classified as obstructed (n = 8) have been surgically confirmed. In the indeterminate (n = 6) and nonobstructed (n = 14) groups, three and two kidneys, respectively, developed obstruction on progress scans. Mean follow-up in the nonsurgical patients was approximately 9 mo (range: 4-17 mo). A total of 13 kidneys had developed obstruction by renographic criteria, and to date 12 have surgical confirmation. Our data indicate that: (1) scans classified as obstructed correlate well with surgery; (2) an initial classification of indeterminate or nonobstructed does not exclude later development of obstruction; and (3) serial scans correctly stratify children with possible uretero-pelvic junction obstruction.

Assessment of hydroureteronephrosis by renographic evaluation under diuretic stimulus.

42 dilated renal units, from 32 patients, were evaluated renographically with 131I, under diuretic stimulus, with the aim of differentiating between obstructed and atonic ureters. The results of this study are similar to the clinical follow-up and surgical findings in 88% of cases.