Pierre Vereerstraeten

Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia Fangchi)

BACKGROUND Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic. METHODS The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated. RESULTS Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46 percent; 95 percent confidence interval, 29 to 62 percent): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma. CONCLUSIONS The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.

Reactivation of hepatitis B after transplantation in patients with pre-existing anti-hepatitis B surface antigen antibodies: report on three cases and review of the literature.

BACKGROUND Patients who have been exposed to the hepatitis B virus (HBV) and who were able to clear the hepatitis B surface antigen from the serum and to develop anti-hepatitis B surface antigen (anti-HBs) antibodies are not considered at risk for HBV reactivation after solid organ transplantation. METHODS AND RESULTS We, however, observed three solid organ transplant recipients who demonstrated clinically significant HBV reactivation after transplantation. All patients presented normal liver enzymes and serological stigmates of healed HBV infection at the time of transplantation, as indicated by the absence of hepatitis B surface antigen and the presence of anti-HBs and anti-hepatitis B core antibodies in the serum. Patient 1, a renal transplant recipient, presented HBV reactivation 3 years after transplantation and developed chronic HBV hepatitis. Patient 2 developed HBV reactivation 7 months after a second cadaveric renal graft and died of cirrhosis four and a half years after transplantation. Patient 3, a heart-lung transplant recipient, developed HBV reactivation within months after transplantation, but died of unrelated causes. HBV reactivation in the presence of anti-HBs antibodies has been previously reported in other settings of immunosuppression, mainly in patients with acquired immunodeficiency syndrome and after bone marrow transplantation, and may lead to fatal liver disease. Data from our renal transplant recipients suggest that the incidence of HBV reactivation among patients with anti-HBs and anti-hepatitis B core antibodies is about 5%. CONCLUSIONS Transplant physicians should be aware of the risk of HBV reactivation in patients presenting with healed HBV infection before transplantation.

The long-term effects of prophylactic OKT3 monoclonal antibody in cadaver kidney transplantation : a single-center, prospective, randomized study

We conducted a randomized, prospective study to determine the long-term effects of prophylactic OKT3 in cadaveric renal transplantation. In the first group of patients (n=56) OKT3 (5 mg/day) was administered for the first 14 postoperative days in association with azathioprine (AZA) and low-dose steroids, cyclosporine (CsA) being introduced on day 11. The other group of patients (n=52) received CsA from the first POD, together with AZA and steroids. Both protocols were identical from POD 14 on. The total number of infections was higher in OKT3 patients (124/1455 patient-months [P-M] vs. 68/1320 in CsA patients, P<0.001) without impact on patient survival (94.5% in OKT3 vs. 93% in CsA patients). OKT3 patients experienced a lower number of rejection episodes (61 per 1455 P-M of risk exposure vs. 81/1320 in CsA patients, P<0.05). In addition, the frequency of corticoresistant rejection episodes was lower in OKT3 patients (9 out of 61 vs. 24 out of 81 in CsA patients, P<0.05). This resulted in a trend toward improved overall graft survival (83% vs. 75%, P=0.12) and in a significant increase in immunological graft survival (92% vs. 79%, P=0.02) in OKT3 patients at 3 years. Taken together, these data suggest that prophylactic OKT3 therapy might have long-term beneficial effects in cadaveric renal transplantation.

Factors related to early mortality in cirrhotic patients bleeding from varices and treated by urgent sclerotherapy.

Variceal haemorrhage in cirrhotic patients carries a high early mortality even when balloon tamponade or emergency sclerotherapy are applied. The aim of this study to identify patients dying within six weeks of their first variceal haemorrhage. One hundred and twenty one patients with parenchymal cirrhosis presenting with the first variceal bleeding episode between June 1983 and December 1988 were studied. Nineteen patients were excluded for various reasons. Emergency sclerotherapy was carried out in cases of active bleeding or where there were endoscopic signs of recent bleeding, and then regularly repeated afterwards. Of the 24 variables studied and included in a multivariate analysis using a logistic regression model, three had an independent prognostic value: encephalopathy, prothrombin time, and the number of blood units transfused within the 72 hours of time zero. The subsequent regression equation was able to predict 89% of the patients who will die and 97% of the patients who will still be alive six weeks after their first variceal haemorrhage treated by sclerotherapy. Pugh score was less discriminatory than these last three variables in terms of accuracy of adjustment, goodness of fit to the model, receiver operating characteristic curves, and percentage correct prediction. To measure the accuracy of the prediction rule, our model was applied to another series of 28 cirrhotic patients admitted with their first variceal bleeding during the next period (January 1989 to May 1990). Death and survival were correctly predicted in respectively 82% and 94% of the cases. The use of this score is recommended for the selection of patients with high early mortality after variceal bleeding despite sclerotherapy, and for the design of new therapeutic trials.

A pilot trial of recombinant human interleukin-10 in kidney transplant recipients receiving OKT3 induction therapy.

BACKGROUND We conducted a randomized, double-blind, placebo-controlled, rising single-dose study to investigate the effects of recombinant human (rh) interleukin (IL) 10 in renal transplant patients who received OKT3 as induction therapy. METHODS Patients received 0.1 (n=6), 1 (n=6), or 10 microg/kg (n=3) rhIL-10 or placebo (n=6) intravenously 30 min before the first injection of 5 mg of OKT3. We monitored IL-10 serum levels, the effect of rhIL-10 on OKT3-induced cytokine production, clinical toxicity, and the incidence of immunization against OKT3. RESULTS Serum IL-10 levels in the three experimental groups reached 0.8+/-0.2, 7.9+/-1.3, and 118.6+/-7.3 ng/ml (mean+/-SEM), respectively, 30 min after rhIL-10 injection. Peak plasma levels of tumor necrosis factor-alpha (TNF-alpha) were reduced from 2953+/-1599 pg/ml in patients injected with OKT3 and placebo to 447+/-155, 703+/-246, and 459+/-246 pg/ml in patients injected with 0.1, 1, and 10 microg/kg rhIL-10, respectively. Values for 24-hr TNF-alpha area under the curve decreased from 8988+/-3551 pg x hr/ml in control patients to 2284+/-494, 3950+/-955, and 2420+/-931 pg x hr/ml for the 0.1, 1, and 10 microg/kg rhIL-10 dose groups, respectively (P=0.045). There was also a trend toward reduced plasma levels of IL-2, IL-8, and interferon-gamma in rhIL-10-pretreated patients. Although none of the patients who received placebo or 0.1 or 1 microg/kg rhIL-10 developed an IgM antibody response directed against OKT3 during the first 10 days, this occurred in all three patients who received the highest rhIL-10 dose. In two of these patients, neutralization of OKT3 was associated with a reversible acute rejection episode. CONCLUSIONS Pretreatment with doses of up to 1 microg/kg rhIL-10 is safe and reduces the release of TNF-alpha induced by OKT3. However, higher doses might promote early sensitization to OKT3.

Persistent Hyperparathyroidism Requiring Surgical Treatment after Kidney Transplantation

There are not many publications describing long-term follow-up of persistent hyperparathyroidism requiring surgical treatment after kidney transplantation (PHSKT). In some patients adenomas, rather than multiglandular disease, have been incriminated as the cause of PHSKT. We reviewed the charts of 45 patients followed for 12 to 146 months (median 45 months) after parathyroidectomy for PHSKT. We compared them with (1) those of 951 patients receiving a kidney graft during the same period but not submitted to parathyroidectomy or (2) 90 matched controls selected from this cohort to determine the characteristics of PHSKT patients. The duration of pretransplant dialysis was significantly longer in PHSKT patients than in controls (5.78 ± 0.41 vs. 3.41 ± 0.24 years; p < 0.0001). A total of 166 glands were removed or biopsied. Except for one questionable case, no true adenoma was observed even when only one gland was enlarged. The outcome of surgery was not influenced by the technique (subtotal parathyroidectomy versus total parathyroidectomy and autografting) but depended on the amount of resected parathyroid tissue: no failures and 4 cases of hypoparathyroidism in 34 cases with no missing gland at cervical exploration; 3 failures and no permanent hypoparathyroidism in 11 cases with one or two missing glands. Excision of the enlarged glands only was sufficient to cure the patient. No recurrence was observed. Our results suggest that single gland enlargement in PHSKT results in most cases from different rates of involution of the parathyroids after successful kidney transplantation. When fewer than four glands are discovered, resection of all visible glands with or without grafting corrects hypercalcemia in more than 70% of the cases.

Intermittent claudication of the hand after creation of an arteriovenous fistula in the forearm

Eighty-five patients were followed up at least 1 year after creation of an arteriovenous fistula in the forearm. The anastomosis was side-to-side in 33 patients, end-to-side in 33 and end-to-end in 19. Trophic lesions were not observed. Intermittent claudication of the hand was more frequent in patients with a side-to-side arteriovenous fistula (42 percent) than in those with end-to-side (21 percent) or end-to-end fistulas (16 percent). Clinical and x-ray studies indicate that two different mechanisms are responsible for cramping pains: arterial steal phenomenon and venous hypertension. Their relative importance depends on multiple hemodynamic factors that may vary with time.

Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the Eurotransplant allocation system.

Although hepatocellular carcinoma (HCC) has become a recognized indication for liver transplantation, the rules governing priority and access to the waiting list are not well defined. Patient‐ and tumor‐related variables were evaluated in 226 patients listed primarily for HCC in Belgium, a region where the allocation system is patient‐driven, priority being given to sicker patients, based on the Child‐Turcotte‐Pugh (CTP) score. Intention‐to‐treat and posttransplantation survival rates at 4 years were 56.5 and 66%, respectively, and overall HCC recurrence rate was 10%. The most significant predictors of failure to receive a transplant in due time were baseline CTP score equal to or above 9 (relative risk [RR] 4.1; confidence interval [CI]: 1.7–9.9) and α fetoprotein above 100 ng/mL (RR 3.0; CI: 1.2–7.1). Independent predictors of posttransplantation mortality were age equal to or above 50 years (RR 2.5; CI: 1.0–3.7) and United Network for Organ Sharing pathological tumor nodule metastasis above the Milan criteria (RR 2.1; CI: 1.0–5.9). Predictors of recurrence (10%) were α fetoprotein above 100 ng/mL (RR 3.2; CI:1.1–10) and vascular involvement of the tumor on the explant (RR 3.6; CI: 1.1–11.3). Assessing the value of the pretransplantation staging by imaging compared to explant pathology revealed 34% accuracy, absence of carcinoma in 8.3%, overstaging in 36.2%, and understaging in 10.4%. Allocation rules for HCC should consider not only tumor characteristics but also the degree of liver impairment. Patients older than 50 years with a stage above the Milan criteria at transplantation have a poorer prognosis after transplantation. Liver Transpl 14:526–533, 2008.

Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the eurotransplant allocation system

Although hepatocellular carcinoma (HCC) has become a recognized indication for liver transplantation, the rules governing priority and access to the waiting list are not well defined. Patient- and tumor-related variables were evaluated in 226 patients listed primarily for HCC in Belgium, a region where the allocation system is patient-driven, priority being given to sicker patients, based on the Child-Turcotte-Pugh (CTP) score, Intention-to-treat and posttransplantation survival rates at 4 years were 56.5 and 66%, respectively, and overall HCC recurrence rate was 10%. The most significant predictors of failure to receive a transplant in due time were baseline CTP score equal to or above 9 (relative risk [RR] 4.1; confidence interval [Cl]: 1.7-9.9) and a fetoprotein above 100 ng/mL (RR 3.0; Cl: 1.2-7.1). Independent predictors of posttransplantation mortality were age equal to or above 50 years (RR 2.5; Cl: 1.0-3.7) and United Network for Organ Sharing pathological tumor nodule metastasis above the Milan criteria (RR 2.1; Cl: 1.0-5.9). Predictors of recurrence (10%) were a fetoprotein above 100 ng/mL (RR 3.2; Cl:1.1-10) and vascular involvement of the tumor on the explant (RR 3.6; Cl: 1.1-11.3). Assessing the value of the pretransplantation staging by imaging compared to explant pathology revealed 34% accuracy, absence of carcinoma in 8.3%, overstaging in 36.2%, and understaging in 10.4%. Allocation rules for HCC should consider not only tumor characteristics but also the degree of liver impairment. Patients older than 50 years with a stage above the Milan criteria at transplantation have a poorer prognosis after transplantation.

Factors influencing survival at one year in patients with nonbiliary hepatic parenchymal cirrhosis

Transplantation may be considered for patients with advanced cirrhosis, however, adequate criteria for evaluating survival in those patients are ill-defined. The aim of the present study was to select, among several clinical and functional variables those that could best predict survival at one year. The data collected from 91 consecutive patients with parenchymal cirrhosis hospitalized in our center from February 1984 to January 1986 were subjected to stepwise logistic regression analysis. Death occurring during the first year following entry into the study was considered as a failure. During that period, there were no censored patients. Of 19 variables that entered into the analysis, only two were significant (P<0.01): presence (1: moderate; 2: severe) or absence (0) of ascites (A) and breath test (BT: % aminopyrine activity of administered dose at 2 hr). The logistic equation was: In (P/1 −P):−1.95 A+1.64 BT−0.393, where Prepresented the probability of survival at one year. For each patient, Pwas calculated according to his Aand BTvalues. Using a 0.7 probability cut-point to separate success from failure, 93% (70/75) of successes, 81% (13/16) of failures, and 91% (83/91) of both successes and failures could be correctly predicted. Predictive equations like the present preliminary one can be used in the future to better assess the risk of mortality in patients with parenchymal cirrhosis in whom liver transplantation is considered.