Eric J. van der Jagt

Anastomotic biliary strictures after liver transplantation: Causes and consequences

We retrospectively studied the prevalence, presentation, results of treatment, and graft and patient survival of grafts developing an anastomotic biliary stricture (AS) in 531 adult liver transplantations performed between 1979 and 2003. Clinical and laboratory information was obtained from the hospital files, and radiological studies were re‐evaluated. Twenty‐one possible risk factors for the development of AS (variables of donor, recipient, surgical procedure, and postoperative course) were analyzed in a univariate and stepwise multivariate model. Forty‐seven grafts showed an anastomotic stricture: 42 in duct‐to‐duct anastomoses, and 5 in hepaticojejunal Roux‐en‐Y anastomoses. The cumulative risk of AS after 1, 5, and 10 years was 6.6%, 10.6%, and 12.3% respectively. Postoperative bile leakage (P = 0.001), a female donor/male recipient combination (P = 0.010), and the era of transplantation (P = 0.006) were independent risk factors for the development of an AS. In 47% of cases, additional (radiologically minor) nonanastomotic strictures were diagnosed. All patients were successfully treated by 1 or more treatment modalities. As primary treatment, endoscopic retrograde cholangiopancreaticography (ERCP) was successful in 24 of 36 (67%) cases and percutaneous transhepatic cholangiodrainage in 4 of 11 (36%). In the end 15 patients (32%) were operated, all with long‐term success. AS presenting more than 6 months after transplantation needed more episodes of stenting by ERCP, and more stents per episode compared to those presenting within 6 months and recurred more often. Graft and patient survival were not impaired by AS. Liver Transpl 12:726–735, 2006.

Nonanastomotic biliary strictures after liver transplantation, part 1: Radiological features and risk factors for early vs. Late presentation

Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). The exact pathogenesis is unclear. Purpose of this study was to identify risk factors for the development of NAS after OLT. A total of 487 adult liver transplants with a median follow‐up of 7.9 years were studied. All imaging studies of the biliary tree were reviewed. Cholangiography was routinely performed between postoperative days 10‐14 and later on demand. Localization of NAS at first presentation was categorized into 4 anatomical zones of the biliary tree. Severity of NAS was semiquantified as mild, moderate, or severe. Donor, recipient, and surgical characteristics and variables were analyzed to identify risk factors for NAS. NAS developed in 81 livers (16.6%). Thirty‐seven (7.3%) were graded as moderate to severe. In 85% of the cases, anatomical localization of NAS was around or below the bifurcation of the common bile duct. A large variation was observed in the time interval between OLT and first presentation of NAS (median 4.1 months; range 0.3‐155 months). NAS presenting early (≤1 year) after OLT were associated with preservation‐related risk factors. Cold and warm ischemia times were significantly longer in patients with early NAS compared with NAS presenting late (>1 year) after OLT (694 minutes vs. 490 minutes, P = 0.01, and 57 minutes vs. 53 minutes, P < 0.05, respectively), and early NAS were more frequently located in the central bile ducts. NAS presenting late (>1 year) after OLT were found more frequently in the periphery of the liver and were more frequently associated with immunological factors, such as primary sclerosing cholangitis, as the indication for OLT (24% vs. 45%, P < 0.05). By separating cases of NAS on the basis of the time of presentation after transplantation, we were able to identify differences in risk factors, indicating different pathogenic mechanisms depending on the time of initial presentation. Liver Transpl 13:708–718, 2007.

Nonanastomotic biliary strictures after liver transplantation, part 2: Management, outcome, and risk factors for disease progression

Nonanastomotic biliary strictures (NAS) after orthotopic liver transplantation (OLT) are associated with high retransplant rates. The aim of the present study was to describe the treatment of and identify risk factors for radiological progression of bile duct abnormalities, recurrent cholangitis, biliary cirrhosis, and retransplantation in patients with NAS. We retrospectively studied 81 cases of NAS. Strictures were classified according to severity and location. Management of strictures was recorded. Possible prognostic factors for bacterial cholangitis, radiological progression of strictures, development of severe fibrosis/cirrhosis, graft survival, and patient survival were evaluated. Median follow‐up after OLT was 7.9 years. NAS were most prevalent in the extrahepatic bile duct. Twenty‐eight patients (35%) underwent some kind of interventional treatment, leading to a marked improvement in biochemistry. Progression of disease was noted in 68% of cases with radiological follow‐up. Radiological progression was more prevalent in patients with early NAS and one or more episodes of bacterial cholangitis. Recurrent bacterial cholangitis (>3 episodes) was more prevalent in patients with a hepaticojejunostomy. Severe fibrosis or cirrhosis developed in 23 cases, especially in cases with biliary abnormalities in the periphery of the liver. Graft survival, but not patient survival, was influenced by the presence of NAS. Thirteen patients (16%) were retransplanted for NAS. In conclusion, especially patients with a hepaticojejunostomy, those with an early diagnosis of NAS, and those with NAS presenting at the level of the peripheral branches of the biliary tree, are at risk for progressive disease with severe outcome. Liver Transpl 13:725–732, 2007.

Positron emission tomography with F-18-fluorodeoxyglucose in a combined staging strategy of esophageal cancer prevents unnecessary surgical explorations

Distant metastases or local invasion are frequently found during the explorative phase of surgery for esophageal cancer. This study was performed to determine the rate of patients with incurable disease encountered during exploration and to examine the impact of preoperative staging, including positron emission tomography (PET), on the number of unnecessary explorations. The records of 203 patients with esophageal cancer who were eligible for curative resection were retrospectively reviewed. The surgical reports were analyzed to obtain the reasons for abandoning resection. Furthermore, the different staging modalities according to the related time interval were reviewed for each patient to analyze the influence of them on the number of explorations. After exploratory surgery, resection was abandoned in 78 of the 203 patients (38%) because of distant metastases (n = 59; 29%), metastatic spread and local irresectability (n = 5; 2%), and local irresectability (n = 14; 7%). In a logistic regression model with all preoperative staging modalities and the year of examination as independent variables, F-18-fluorodeoxyglucose (FDG)-PET) was the only modality that predicts intended curative resection in these patients (P < 0.001). In patients with esophageal cancer who are suitable for potentially curative surgery, resection was abandoned mainly because of distant metastases encountered during exploration. The addition of FDG-PET may have reduced the rate of unnecessary surgery in this group of patients.

Association of Urinary Biomarkers With Disease Severity in Patients With Autosomal Dominant Polycystic Kidney Disease: A Cross-sectional Analysis

BACKGROUND Disease monitoring of autosomal dominant polycystic kidney disease (ADPKD) will become more important with potential upcoming therapeutic interventions. Because serum creatinine level is considered of limited use and measurement of effective renal blood flow (ERBF) and total renal volume are time consuming and expensive, there is a need for other biomarkers. We aimed to investigate which urinary markers have increased levels in patients with ADPKD; whether these urinary markers are associated with measured glomerular filtration rate (mGFR), ERBF, and total renal volume; and whether these associations are independent of albuminuria (urine albumin excretion [UAE]). STUDY DESIGN Diagnostic test study. SETTING & PARTICIPANTS 102 patients with ADPKD (Ravine criteria) and 102 age- and sex-matched healthy controls. INDEX TEST 24-hour urinary excretion of glomerular (immunoglobulin G), proximal tubular (kidney injury molecule 1 [KIM-1], N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin [NGAL], and β(2)-microglobulin), and distal tubular (heart-type fatty acid binding protein [H-FABP]) damage markers and inflammatory markers (monocyte chemotactic protein 1 [MCP-1] and macrophage migration inhibitory factor). REFERENCE TEST Disease severity assessed using measures of kidney function (mGFR and ERBF, measured using clearance of iothalamate labeled with iodine 125 and hippuran labeled with iodine 131 during continuous infusion, respectively) and structure (total renal volume, measured using magnetic resonance imaging). OTHER MEASUREMENTS 24-hour UAE. RESULTS In 102 patients with ADPKD (aged 40 ± 11 years; 58% men), levels of all measured urinary biomarkers were increased compared with healthy controls. Excretion of immunoglobulin G and albumin relatively were most increased. ERBF and mGFR values were associated with urinary excretion of β(2)-microglobulin, NGAL, and H-FABP independent of UAE, whereas total renal volume was associated with KIM-1, NGAL, and MCP-1 independent of UAE. LIMITATIONS Cross-sectional, single center. CONCLUSIONS Levels of markers for multiple parts of the nephron are increased in patients with ADPKD. In addition to measurement of UAE, measurement of urinary β(2)-microglobulin, KIM-1, H-FABP, MCP-1, and especially NGAL could be of value for determination of disease severity in patients with ADPKD.

Prospective Comparison of [18F]Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography in Patients With Melanoma With Palpable Lymph Node Metastases: Diagnostic Accuracy and Impact on Treatment

PURPOSE Patients with melanoma with potentially resectable lymph node metastases require accurate staging to prevent unnecessary surgery. [(18)F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) is attractive for this because melanoma typically is FDG avid. The aim of this prospective multicenter study was to perform a head-to-head comparison of FDG-PET and computed tomography (CT) in staging of patients with melanoma with palpable lymph node metastases in terms of diagnostic accuracy and impact on treatment. PATIENTS AND METHODS All consecutive patients with palpable, proven lymph node metastases of melanoma between mid 2003 and 2007 were prospectively included. The number/site of distant metastases detected with FDG-PET and CT were recorded. Histology/cytology or 6 months follow-up were the reference standard. Intended and performed treatment was recorded. RESULTS Distant metastases were suspected by FDG-PET in 32% of the 251 patients and by CT in 29% (P = .26). Upstaging was correct in 27% by FDG-PET and in 24% by CT (P = .18). FDG-PET detected more metastatic sites (133 v 112, P = .03), detecting significantly more bone and subcutaneous metastases. Treatment changed in 19% of patients; in 79% as a result of both scans, in 17% exclusively by FDG-PET, and in 4% exclusively by CT. In 34 patients (14%), FDG-PET had an additional value over spiral CT, and in 23 patients (9%), CT had additional value over FDG-PET. CONCLUSION As a result of FDG-PET and CT, 27% of patients were upstaged, and treatment changed in one of five patients. FDG-PET and CT are equivalent in upstaging; however, FDG-PET detected more metastatic sites, especially bone and subcutaneous. FDG-PET and/or CT are indicated in the staging of patients with melanoma with palpable lymph node metastases.

Copeptin, a Surrogate Marker of Vasopressin, Is Associated with Disease Severity in Autosomal Dominant Polycystic Kidney Disease

BACKGROUND AND OBJECTIVES Experimental studies suggest a detrimental role for vasopressin in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, it is unknown whether endogenous vasopressin concentration is associated with disease severity in patients with ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Plasma copeptin concentration (a marker of endogenous vasopressin levels) was measured in 102 ADPKD patients (diagnosis based on Ravine criteria) by an immunoassay. Plasma and urinary osmolarity were also measured. To assess disease severity, GFR and effective renal blood flow were measured by continuous infusion of 125I-iothalamate and 131I-hippuran, total renal volume by magnetic resonance imaging, and 24-hour urinary albumin excretion by nephelometry. RESULTS In these ADPKD patients, copeptin was associated with the various markers of disease severity in ADPKD (positively with total renal volume [R=0.47] and albuminuria [R=0.39] and negatively with GFR [R=-0.58] and effective renal blood flow [R=-0.52], all P<0.001). These associations were independent of age, gender, and use of diuretics. Copeptin was furthermore associated with plasma osmolarity (P<0.001) but not with 24-hour urinary volume, 24-hour urinary osmolarity or fractional urea excretion (P=0.7, 0.9, and 0.3, respectively). CONCLUSIONS On cross-sectional analysis, copeptin is associated with disease severity in ADPKD patients, supporting the results of experimental studies that suggest that vasopressin antagonists have a renoprotective effect in ADPKD and offering a good prospect for clinical studies with these agents.

Consequences of additional use of PET information for target volume delineation and radiotherapy dose distribution for esophageal cancer

BACKGROUND AND PURPOSE To determine the consequences of target volume (TV) modifications, based on the additional use of PET information, on radiation planning, assuming PET/CT-imaging represents the true extent of the tumour. MATERIALS AND METHODS For 21 patients with esophageal cancer, two separate TVs were retrospectively defined based on CT (CT-TV) and co-registered PET/CT images (PET/CT-TV). Two 3D-CRT plans (prescribed dose 50.4 Gy) were constructed to cover the corresponding TVs. Subsequently, these plans were compared for target coverage, normal tissue dose-volume histograms and the corresponding normal tissue complication probability (NTCP) values. RESULTS The addition of PET led to the modification of CT-TV with at least 10% in 12 of 21 patients (57%) (reduction in 9, enlargement in 3). PET/CT-TV was inadequately covered by the CT-based treatment plan in 8 patients (36%). Treatment plan modifications resulted in significant changes (p<0.05) in dose distributions to heart and lungs. Corresponding changes in NTCP values ranged from -3% to +2% for radiation pneumonitis and from -0.2% to +1.2% for cardiac mortality. CONCLUSIONS This study demonstrated that TVs based on CT might exclude PET-avid disease. Consequences are under dosing and thereby possibly ineffective treatment. Moreover, the addition of PET in radiation planning might result in clinical important changes in NTCP.

Early Renal Abnormalities in Autosomal Dominant Polycystic Kidney Disease

BACKGROUND AND OBJECTIVES Potential therapeutic interventions are being developed for autosomal dominant polycystic kidney disease (ADPKD). A pivotal question will be when to initiate such treatment, and monitoring disease progression will thus become more important. Therefore, the prevalence of renal abnormalities in ADPKD at different ages was evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Included were 103 prevalent ADPKD patients (Ravine criteria). Measured were mean arterial pressure (MAP), total renal volume (TRV), GFR, effective renal plasma flow (ERPF), renal vascular resistance (RVR), and filtration fraction (FF). Twenty-four-hour urine was collected. ADPKD patients were compared with age- and gender-matched healthy controls. RESULTS Patients and controls were subdivided into quartiles of age (median ages 28, 37, 42, and 52 years). Patients in the first quartile of age had almost the same GFR when compared with controls, but already a markedly decreased ERPF and an increased FF (GFR 117 +/- 32 versus 129 +/- 17 ml/min, ERPF 374 +/- 119 versus 527 +/- 83 ml/min, FF 32% +/- 4% versus 25% +/- 2%, and RVR 12 (10 to 16) versus 8 (7 to 8) dynes/cm(2), respectively). Young adult ADPKD patients also had higher 24-hour urinary volumes, lower 24-hour urinary osmolarity, and higher urinary albumin excretion (UAE) than healthy controls, although TRV in these young adult patients was modestly enlarged (median 1.0 L). CONCLUSIONS Already at young adult age, ADPKD patients have marked renal abnormalities, including a decreased ERPF and increased FF and UAE, despite modestly enlarged TRV and near-normal GFR. ERPF, FF, and UAE may thus be better markers for disease severity than GFR.

Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function

BACKGROUND A recent study showed that tolvaptan, a vasopressin V2 receptor antagonist, decreased total kidney volume (TKV) growth and estimated glomerular filtration rate (GFR) loss in autosomal dominant polycystic kidney disease (ADPKD) with creatinine clearance≥60mL/min. The aim of our study was to determine whether the renal hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR. STUDY DESIGN Clinical trial with comparisons before and after treatment. SETTING & PARTICIPANTS Patients with ADPKD with a wide range of measured GFRs (mGFRs; 18-148 mL/min) in a hospital setting. INTERVENTION Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120mg/d in weeks 1, 2, and 3, respectively). OUTCOMES Change in markers for aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers). MEASUREMENTS GFR was measured by (125)I-iothalamate clearance; TKV, by magnetic resonance imaging; biomarker excretion, by enzyme-linked immunosorbent assay; and osmolality, by freezing point depression. RESULTS In 27 participants (52% men; aged 46±10 years; mGFR, 69±39mL/min; TKV, 2.15 [IQR, 1.10-2.77] L), treatment with tolvaptan led to an increase in urine volume and free-water clearance and a decrease in urine osmolality, TKV, and kidney injury marker excretion. Changes in urine volume and osmolality with treatment were less in participants with lower baseline mGFRs (both P<0.01). However, change in fractional free-water clearance was greater at lower baseline mGFRs (P=0.001), suggesting that participants with decreased GFRs responded more to tolvaptan per functioning nephron. LIMITATIONS Limited sample size, no control group. CONCLUSIONS In patients with ADPKD with decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs.