Percutaneous transhepatic biliary drainage in an infant with obstructive jaundice caused by neuroblastoma.

Neuroblastoma presenting with obstructive jaundice is a rare event. Management of this condition includes surgery, chemotherapy, radiotherapy, temporary cholecystostomy tube, endoscopic retrograde cholangiopancreatography (ERCP), and internal biliary drainage (IBD). We herein describe our experience with one infant affected by neuroblastoma presenting with jaundice, who successfully underwent percutaneous transhepatic biliary drainage (PTBD). This report introduces PTBD as a viable treatment option for neuroblastoma and obstructive jaundice and provides a review of the pertinent literature.

Intermediate volume on computed tomography imaging defines a fibrotic compartment that predicts glomerular filtration rate decline in autosomal dominant polycystic kidney disease patients.

Total kidney and cyst volumes have been used to quantify disease progression in autosomal dominant polycystic kidney disease (ADPKD), but a causal relationship with progression to renal failure has not been demonstrated. Advanced image processing recently allowed to quantify extracystic tissue, and to identify an additional tissue component named "intermediate," appearing hypoenhanced on contrast-enhanced computed tomography (CT). The aim of this study is to provide a histological characterization of intermediate volume, investigate its relation with renal function, and provide preliminary evidence of its role in long-term prediction of functional loss. Three ADPKD patients underwent contrast-enhanced CT scans before nephrectomy. Histological samples of intermediate volume were drawn from the excised kidneys, and stained with hematoxylin and eosin and with saturated picrosirius solution for histological analysis. Intermediate volume showed major structural changes, characterized by tubular dilation and atrophy, microcysts, inflammatory cell infiltrate, vascular sclerosis, and extended peritubular interstitial fibrosis. A significant correlation (r = -0.69, P < 0.001) between relative intermediate volume and baseline renal function was found in 21 ADPKD patients. Long-term prediction of renal functional loss was investigated in an independent cohort of 13 ADPKD patients, followed for 3 to 8 years. Intermediate volume, but not total kidney or cyst volume, significantly correlated with glomerular filtration rate decline (r = -0.79, P < 0.005). These findings suggest that intermediate volume may represent a suitable surrogate marker of ADPKD progression and a novel therapeutic target.

Sirolimus therapy to halt the progression of ADPKD.

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR>or=40 ml/min per 1.73 m2. In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46+/-81 ml; P=0.047) than on conventional therapy (70+/-72 ml; P=0.002), but we did not detect a difference between the two treatments (P=0.45). Cyst volume was stable on sirolimus and increased by 55+/-75 ml (P=0.013) on conventional therapy, whereas parenchymal volume increased by 26+/-30 ml (P=0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4.

BACKGROUND AND OBJECTIVES: The effect of mammalian target of rapamycin (mTOR) inhibitors has never been tested in patients with autosomal dominant polycystic kidney disease (ADPKD) and severe renal insufficiency. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this academic, prospective, randomized, open label, blinded end point, parallel group trial (ClinicalTrials.gov no. NCT01223755), 41 adults with ADPKD, CKD stage 3b or 4, and proteinuria ≤0.5 g/24 h were randomized between September of 2010 and March of 2012 to sirolimus (3 mg/d; serum target levels of 5-10 ng/ml) added on to conventional therapy (n=21) or conventional treatment alone (n=20). Primary outcome was GFR (iohexol plasma clearance) change at 1 and 3 years versus baseline. RESULTS: At the 1-year preplanned interim analysis, GFR fell from 26.7±5.8 to 21.3±6.3 ml/min per 1.73 m(2) (P<0.001) and from 29.6±5.6 to 24.9±6.2 ml/min per 1.73 m(2) (P<0.001) in the sirolimus and conventional treatment groups, respectively. Albuminuria (73.8±81.8 versus 154.9±152.9 µg/min; P=0.02) and proteinuria (0.3±0.2 versus 06±0.4 g/24 h; P<0.01) increased with sirolimus. Seven patients on sirolimus versus one control had de novo proteinuria (P=0.04), ten versus three patients doubled proteinuria (P=0.02), 18 versus 11 patients had peripheral edema (P=0.04), and 14 versus six patients had upper respiratory tract infections (P=0.03). Three patients on sirolimus had angioedema, 14 patients had aphthous stomatitis, and seven patients had acne (P<0.01 for both versus controls). Two patients progressed to ESRD, and two patients withdrew because of worsening of proteinuria. These events were not observed in controls. Thus, the independent data and safety monitoring board recommend early trial termination for safety reasons. At 1 year, total kidney volume (assessed by contrast-enhanced computed tomography imaging) increased by 9.0% from 2857.7±1447.3 to 3094.6±1519.5 ml on sirolimus and 4.3% from 3123.4±1695.3 to 3222.6±1651.4 ml on conventional therapy (P=0.12). On follow-up, 37% and 7% of serum sirolimus levels fell below or exceeded the therapeutic range, respectively. CONCLUSIONS: Finding that sirolimus was unsafe and ineffective in patients with ADPKD and renal insufficiency suggests that mTOR inhibitor therapy may be contraindicated in this context.

Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide.

BACKGROUND AND OBJECTIVES: No medical treatment is available for polycystic liver disease, a frequent manifestation of autosomal-dominant polycystic kidney disease (ADPKD). In a prospective, randomized, double-blind, crossover study, 6 months of octreotide (40 mg every 28 days) therapy limited kidney volume growth more effectively than placebo in 12 patients with ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this secondary, post hoc analysis of the above study, octreotide-induced changes in liver volumes compared with placebo and the relationship between concomitant changes in liver and kidney volumes were evaluated. Those analyzing liver and kidney volumes were blinded to treatment. RESULTS: Liver volumes significantly decreased from 1595 +/- 478 ml to 1524 +/- 453 ml with octreotide whereas they did not appreciably change with placebo. Changes in liver volumes were significantly different between the two treatment periods (-71 +/- 57 ml versus +14 +/- 85 ml). Octreotide-induced liver volume reduction was fully explained by a reduction in parenchyma volume from 1506 +/- 431 ml to 1432 +/- 403 ml. Changes in liver volumes were significantly correlated with concomitant changes in kidney volumes (r = 0.67) during octreotide but not during placebo treatment. Liver and kidney volume changes significantly differed with both treatments (octreotide: -71 +/- 57 ml versus +71 +/- 107; placebo: +14 +/- 85 ml versus +162 +/- 114), but net reductions in liver (-85 +/- 103 ml) and kidney (-91 +/- 125 ml) volume growth on octreotide versus placebo were similar. CONCLUSIONS: Octreotide therapy reduces liver volumes in patients with ADPKD and is safe.

Computed tomography evaluation of autosomal dominant polycystic kidney disease progression: a progress report.

At the moment, there are no effective therapies to prevent or slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Radiologic evaluations are used to monitor volume of renal cysts and parenchyma during disease evolution. Volumetric quantifications based on computed tomography were used to investigate the relation between structural and functional changes in patients with advanced-stage ADPKD. By use of image-processing techniques, volume of kidneys, renal cysts, fully enhanced parenchyma, and faintly contrast-enhanced parenchyma, referred to as intermediate, was estimated. GFR measurements and computed tomography evaluations were repeated 6 mo later. No statistically significant correlations were found between volumes of cysts and parenchyma and intermediate volume and GFR. However, the ratio of intermediate over parenchymal volume strongly correlated with GFR (r = -0.81, P < 0.001). In addition, there were significant correlations between percentage changes in intermediate volume (absolute or relative to parenchyma) and GFR changes during the observation period (r = -0.70 and r = -0.75, P < 0.01). These data support the hypothesis of a significant relation between radiologic appearance of renal structure and functional changes and suggest new ways that renal dysfunction in ADPKD may be predicted. Further work is necessary to determine the nature of faintly contrast-enhanced parenchyma and its role in renal functional loss.

Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease.

BACKGROUND: The fluid filling renal cysts in human polycystic kidneys is secreted chiefly by the tubular epithelium lining the cysts via secondary chloride transport. Inhibiting this process by somatostatin therapy should induce shrinking of renal cysts. METHODS: In this randomized, cross-over, placebo-controlled trial we compared the risk/benefit profile of 6-month treatment with long-acting somatostatin (octreotide-LAR, 40 mg intramuscularly every 28 days) or placebo in autosomal-dominant polycystic kidney disease (ADPKD) patients with mild-to-moderate renal insufficiency and no evidence of other kidney disease. Volumes of kidney structures were evaluated by a two-slice computed tomography (CT) scanner; while glomerular filtration rate (GFR) was estimated by iohexol plasma clearance. RESULTS: One patient on somatostatin and one on placebo were prematurely withdrawn because of nonsymptomatic, reversible colelithiasis and asthenia, respectively. In the remaining 12 patients somatostatin was well tolerated. Kidney volume increased by 71 +/- 107 mL (P < 0.05) on somatostatin and by 162 +/- 114 mL (P < 0.01) on placebo. The percent increase was significantly lower on somatostatin (2.2 +/- 3.7% vs. 5.9 +/- 5.4%) (P < 0.05). Cystic volume tended to increase less on somatostatin than on placebo (3.0 +/- 6.5% vs. 5.6 +/- 5.8%). The "parenchymal" volume nonsignificantly increased by 2.5 +/- 8.4% on placebo and slightly decreased by 4.4 +/- 8.9% on somatostatin. The GFR did not change significantly during both treatment periods. CONCLUSION: In ADPKD patients, 6-month somatostatin therapy is safe and may slow renal volume expansion. This may reflect an inhibited growth in particular of smallest cysts beyond the detection threshold of CT scan evaluation. Whether this effect may prove renoprotective in the long term should be tested in additional trials of longer duration.