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Despite improving overall results of pediatric renal transplantation children under 5 years of age remain a high-risk group with poorer outcomes often because of a higher rate of surgical complications. This retrospective report details a 12-year experience at a single center and examines the outcome in this high-risk group of patients. We reviewed the medical records of 21 children under 5 years of age who received renal transplantation at Loma Linda University Medical Center between July 1988 and August 2000. The patients were evaluated regularly by the same pediatric nephrologist throughout the study period at our outpatient clinic. Mean recipient age was 3 +/- 1.2 (range 2-5) years; weight at transplantation was 13.3 +/- 5.4 kg. Ten (48%) patients received living related donor (LRD) kidneys and 11 (52%) received cadaver (CAD) kidneys. Mean donor ages for CAD and LRD were 14.4 +/- 10 years and 26.6 +/- 4.9 years, respectively. The mean cold ischemia time (CAD only) was 23.3 +/- 10.6 hours. Renal dysplasia (n = 8) and obstructive uropathy (n = 5) were the most common primary diagnoses. Maintenance immunosuppression consisted of Azathioprine or mycophenolate mofetil (MMF), cyclosporine or tacrolimus and prednisone. Mean follow-up was 80.1 +/- 51.4 months. Twelve (57%) grafts have a follow-up >5 years. Patient survival was 100 per cent. Overall graft survival at one, 3, 5, and 10 years were 95, 95, 88, and 88 per cent respectively. Graft survival for LRD recipients was 100 per cent. No graft was lost as a result of a technical problem or vascular thrombosis. One graft each was lost because of delayed graft function complicated by severe cytomegalovirus infection and chronic rejection. At one year the mean serum creatinine was 0.6 +/- 0.2 mg/dL with a mean calculated glomerular filtration rate of 93 +/- 32 mL/min. All 17 children who are now of school age are attending school. We conclude that excellent rehabilitation and superior long-term patient and graft survival can be achieved with renal transplantation in children of this age group with the use of good surgical techniques and close follow-up.
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PMID:Superior long-term results of renal transplantation in children under 5 years of age. 1251 21

Late hepatic artery thrombosis (HAT) is a rare complication after orthotopic liver transplantation (OLT), conventionally described as occurring more than 30 days after surgery. Only a few reports document its course. In a consecutive series of 634 OLTs (704 grafts), 11 patients (1.7%) had late HAT, diagnosed a median of 6 months (range, 1.8 to 79 months) after OLT. Clinical variables were compared with those of 415 patients without HAT who had a complete database and follow-up, including cytomegalovirus (CMV) surveillance. At presentation, 11 patients had fever, 4 patients had jaundice. Hepatic abscesses were present in 6 patients (3 patients with biliary leak), 4 patients had biliary tree necrosis (2 patients with biliary leak), and 1 patient had no biliary complications. Five patients (45%) underwent accessory hepatic artery anastomosis versus 73 patients (17%) without HAT (P <.05). Five patients (45%) with late HAT had CMV infection versus 14% without HAT (P <.05). Two episodes of late HAT (11 and 79 months) occurred in patients who underwent re-OLT for early HAT (3.9%). Re-OLT was performed in 8 patients a median of 11 days (range, 3 to 37 days) after diagnosis (preceded by intravenous antibiotics and percutaneous drainage). The other 3 patients underwent partial hepatectomy (1 patient), external percutaneous drainage as unfit for surgery (1 patient), and antibiotic therapy only (1 patient). Death occurred in 4 patients who underwent re-OLT (50%) because of septicemia at 11, 23, and 60 days after re-OLT and 17 days after a third OLT. There was one late death (30 months) after partial hepatectomy (hepatitis C recurrence) and one death 6 months after long-term biliary drainage because of sepsis. The 5 survivors have good health with normal liver function test results at a median 52 months (range, 6 to 57 months). In conclusion, late HAT presents with fever caused by hepatic abscesses or biliary leak associated with biliary ischemia and necrosis. CMV infection and accessory hepatic artery anastomosis are risk factors for late HAT in our cohort. Early intervention followed by re-OLT can salvage patients.
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PMID:Late hepatic artery thrombosis after orthotopic liver transplantation. 1278 3

Seronegative transplant recipients are at a high risk of developing primary cytomegalovirus (CMV) infection. The D+/R--constellation produces a 60%-80% probability of CMV disease. In such cases CMV prophylaxis is justified. Presentation of a 12-year old boy who developed a primary CMV infection following A combined liver-kidney transplantation; evaluation of prophylactic options and review of some difficulties in the diagnosis of CMV infection. A cadaveric liver-kidney transplantation (Tx) was done in a 12-year old boy with ESRD due to type I primary hyperoxaluria. CMV status: D+, R-; number of mismatches: 5. PRA 0; kidney cold ischemia time (CIT): 13.54 h; liver CIT: 10.10 h; immediate diuresis; Immunosuppression protocol: anti IL-2 receptor antibodies, steroids, mycophenolate mofetil (MMF); cyclosporine introduced on day 6. Over the first week, daily hemodialyses were done in order to remove oxalate deposits. Kidney and liver biopsies: no ACR, no oxalate deposits. CMV prophylaxis with ganciclovir started on day 0. Routine serology and PCR for CMV follow-up showed: pp 65, IgM and IgG, CMV. DNA (Murex CMV. DNA Hybrid Capture test 2.0): negative over the first 3 months. Day 98: CMV pp 65 positive, IgM neg, DNA neg. Day 108: pp 65 neg, IgM positive, IgG neg. CMV. DNA positive (15 x 105 copies/ml). Clinical status: except for mild Cushing, liver tests and kidney function were normal. Ganciclovir was administered intravenously (i.v.) and after 14 days continued perorally. A few days later, leukopenia with severe neutropenia (neutrophil count: 400) and right otitis media developed. MMF and ganciclovir were withdrawn for a few days and reintroduced after WBC count reconstitution. We had no possibility to monitor MMF. Day 150 pp 65 neg, IgM still positive, IgG neg. No clinical signs of infection. Liver and kidney functions normal. After liver-kidney transplantation in a CMV high-risk pediatric patient (D+/R-), asymptomatic CMV primary infection developed. Although ganciclovir prophylaxis could not prevent the infection, it was mild and delayed. Due to bone marrow suppression, discontinuation of MMF and ganciclovir was necessary. Antigenemia assay pp 65 did not correlate very well with CMV viremia so it could not be recommended as a routine test. It should be used in combination with other CMV tests.
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PMID:[Primary cytomegalovirus infection after combined cadaveric transplantation of the liver and kidney]. 1287 72

Cholestasis is a common sequela of liver transplantation. Although the majority of cases remain subclinical, severe cholestasis may be associated with irreversible liver damage, requiring retransplantation. Therefore, it is essential that clinicians be able to identify and treat the syndromes associated with cholestasis. In this review, we consider causes of intrahepatic cholestasis. These may be categorized by time of occurrence, namely, within 6 months of liver transplantation (early) and thereafter (late), although there may be an overlap in their causes. The causes of intrahepatic cholestasis include ischemia/reperfusion injury, bacterial infection, acute cellular rejection, cytomegalovirus infection, small-for-size graft, drugs for hepatotoxicity, intrahepatic biliary strictures, chronic rejection, hepatic artery thrombosis, ABO blood group incompatibility, and recurrent disease. The mechanisms of cholestasis in each category and the clinical presentation, diagnosis, treatment, and outcome are discussed in detail.
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PMID:Intrahepatic cholestasis after liver transplantation. 1452 93

Angiogenic gene therapy for stable angina is aimed at promoting new blood vessel formation in the heart, thus providing enhanced cardiac perfusion, symptom relief, increased exercise capacity, improved quality of life, and reduced risk of coronary events. Ad5FGF-4 is a replication-deficient serotype 5 adenovirus encoding the gene for fibroblast growth factor-4 (FGF-4) driven by a cytomegalovirus promoter. In preclinical studies using a pig model of myocardial ischemia, a single intracoronary infusion of Ad5FGF-4 improved cardiac contractile function and regional blood flow in the ischemic region during stress. These effects were apparent after 2 weeks and maintained for > or =12 weeks. Histologic evidence of capillary angiogenesis was observed. FGF-4 gene expression was detected in the heart but not at extracardiac sites. Placebo-controlled trials in humans with chronic stable angina indicate that Ad5FGF-4 increases treadmill exercise duration and improves stress-related ischemia measured by perfusion sestamibi single-photon emission computed tomography. More patients receiving Ad5FGF-4 than placebo reported complete resolution of their angina and no nitroglycerin use. Ad5FGF-4 gene therapy was well tolerated. The administration procedure did not cause any adverse events, although mild, transient fever, a transient modest fall in platelet count, and a transient mild elevation in hepatic enzymes and uric acid levels occurred in a few patients. This adverse event profile concurs with other adenoviral gene trials. There was no evidence of myocarditis, retinal neovascularization, or angioma formation. FGF-4 was not detected in venous blood. Larger clinical trials will assess Ad5FGF-4 with regard to cardiovascular prognosis, symptom relief, and safety profile in patients with chronic stable angina.
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PMID:Angiogenic gene therapy with adenovirus 5 fibroblast growth factor-4 (Ad5FGF-4): a new option for the treatment of coronary artery disease. 1461 23

Transplanted patients are susceptible to viral infections; thus, the aim of this study was to evaluate the features of acute rejections and the outcome of the renal graft in transplanted patients with herpes virus diseases. Renal biopsies from 30 renal transplanted patients undergoing early acute rejection (type IA and IB according to the Banff 97 classification) were evaluated. In total, 15 of these patients experienced cytomegalovirus (CMV) or Epstein-Barr virus disease within the first year following transplantation (group I) and 15 patients showed no evidence of viral infection (group II). No significant differences between the groups in terms of age, male/female ratio, living/cadaveric donor ratio, cold ischemia time, HLA A-B matching, pretransplant panel reactive antibody test, occurrence of post-transplant tubular necrosis, plasma levels of cyclosporin A and mean percent increase of serum creatinine at the time of the biopsy were observed. In group I biopsies, the mean number of interstitial plasma cells, as well as the mean number of CD79a-positive cells (B lymphocytes and plasma cells) was significantly higher than in group II (P<0.01 and <0.01, respectively). There was a positive correlation between the number of infections and the number of plasma cells (P<0.05). In transplanted patients, CMV can trigger the formation of anti-endothelial cell antibodies, which have been proposed to play a role in antibody-mediated rejections. We investigated whether a deposition of C4d, a marker of antibody-mediated reactions, was present in renal peritubular capillaries. In group I C4d deposition was found in five cases, while in group II it was not observed (P<0.05). In group I, 7/15 patients developed chronic allograft nephropathy vs 1/15 patients in group II (P<0.05). The estimated 1-, 5- and 8-year cumulative graft survival rates were 80, 66 and 57%, respectively, in group I, while in group II the estimated 8-year cumulative survival rate was 100% (P<0.05). In conclusion, acute rejection biopsies of patients with viral infections displayed plasma cell infiltrates and, in several cases, C4d deposition. Our study suggests a role of B lymphocytes in the pathology of these rejections and confirms the association between viral infections and poor graft survival.
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PMID:Acute rejection and graft survival in renal transplanted patients with viral diseases. 1537 53

Various regions of the brain have been successfully transduced by recombinant adeno-associated virus (rAAV) vectors with no detected toxicity. When using the cytomegalovirus immediate early (CMV) promoter, a gradual decline in the number of transduced cells has been described. In contrast, the use of cellular promoters such as the neuron-specific enolase promoter or hybrid promoters such as the chicken beta-actin/CMV promoter resulted in sustained transgene expression. The cellular tropism of rAAV-mediated gene transfer in the central nervous system (CNS) varies depending on the serotype used. Serotype 2 vectors preferentially transduce neurons whereas rAAV5 and rAAV1 transduce both neurons and glial cells. Recombinant AAV4-mediated gene transfer was inefficient in neurons and glial cells of the striatum (the only structure tested so far) but efficient in ependymal cells. No inflammatory response has been described following rAAV2 administration to the brain. In contrast, antibodies to AAV2 capsid and transgene product were elicited but no reduction of transgene expression was observed and readministration of vector without loss of efficiency was possible from 3 months after the first injection. Based on the success of pioneer work performed with marker genes, various strategies for therapeutic gene delivery were designed. These include enzyme replacement in lysosomal storage diseases, Canavan disease and Parkinson's disease; delivery of neuroprotective factors in Parkinson's disease, Huntington disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemia and spinal cord injury; as well as modulation of neurotransmission in epilepsy and Parkinson's disease. Several of these strategies have demonstrated promising results in relevant animal models. However, their implementation in the clinics will probably require a tight regulation and a specific targeting of therapeutic gene expression which still demands further developments of the vectors.
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PMID:Recombinant AAV-mediated gene delivery to the central nervous system. 1497 64

Improvements in MRI techniques widen the indications for fetal brain imaging and fetal brain injury represents the third indication of fetal brain magnetic resonance imaging (MRI) after the evaluation of suspected central nervous system (CNS) malformations and ventricular dilatation. Optimal MR imaging technique is necessary in order to collect as much data as possible about the fetal brain. Diffusion images can be used routinely in addition to the standard protocol of fetal brain MRI that consists of T1 and T2 weighted images of the fetal brain. Monovoxel proton magnetic resonance spectroscopy can also be performed in utero, but this technique is still more part of research protocol than of routine clinical protocol. Fetal brain injury includes hypoxia-ischemia, congenital infections (especially toxoplasmosis and cytomegalovirus infections), brain damage due to malformation such as vascular brain malformation and heart malformation, pregnancies at risk of fetal brain damage, and even inherited metabolic diseases, especially mitochondrial diseases. MRI findings in fetal brain injury consist of acute or chronic lesions that can be seen alone or in combination. Acute response of the fetal brain is less commonly seen than the chronic response compared to the brain response encountered in the postnatal period.
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PMID:Fetal brain injury. 1509 50

The aim of this study was to assess the prevalence clinical presentation, and impact on outcome of late hepatic artery thrombosis (HAT) after OLT. We also sought risk factors other than technical problems that predispose to the pathogenesis of late HAT among 178 OLT performed from 1999 to 2002. Late HAT was diagnosed using Doppler ultrasonography and arteriography. Late HAT was observed in nine patients (3.8%), all of whom had experienced chronic HCV infection. Median time to HAT diagnosis was 4.88 months after OLT. Mean follow-up time was 40.25 months. Recipient age ranged from 30 to 61 years and median donor age, 28 years. Mean warm ischemia time was 63 minutes and mean cold ischemia time, 660 minutes. All of our study group were cigarette smokers. Postoperative CMV infection, presenting with hepatitis, had been treated in 55.6%. Before the diagnosis of HAT more than one episode of acute cellular rejection had been observed in six patients (55.6%) and 44.5% had chronic rejection. The diagnosis of CR was established after the diagnosis of HAT in all cases. Recurrence of HCV infection was histologically documented in 44.5%. Only one patient experienced graft loss (77 months after OLT). Six of nine patients had biliary complications, treated either by endoscopic stenting or by surgical drainage. Two patients were asymptomatic. In conclusion, late HAT shows a benign presentation that has no impact on graft survival. Possible risk factors have yet to be defined by multicenter trials.
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PMID:Late hepatic artery thrombosis after liver transplantation: clinical setting and risk factors. 1519 36

Determinants of progression to cirrhosis in hepatitis C virus (HCV) infection have been well described in the immunocompetent population but remain poorly defined in liver transplant (LT) recipients. This cohort study determines the factors contributing to the development of fibrosis and its rate of progression in the allograft. Predictive factors analyzed include: demographics, host and donor factors, surgery-related variables (cold and warm ischemia time), rejection episodes, cytomegalovirus infection (CMV), and immunosuppression. Over 12 years, 842 adult LTs were performed at our institution; 358 for the indication of HCV. A total of 264 patients underwent protocol liver biopsies at month 4 and yearly after LT. Using the modified Knodell system of Ishak for staging fibrosis, the median fibrosis progression rate was .8 units/year (P < .001). Rapid fibrosis progression (> .8 units/year) was best identified by liver histology performed at 1 year. Donor age > 55 years was associated with rapid fibrosis progression and development of cirrhosis (P < .001). In contrast, donor age < 35 years was associated with slower progression of fibrosis (P = .003). Risk factors for graft loss due to recurrent HCV included recipient age > 35 years (P = .01), donor age > 55 years (P = .005), and use of female donor allografts (P = .03). In conclusion, fibrosis progression in HCV-infected LT recipients occurs at a rate of .8 units/year. Increased donor age has a major impact on disease progression, graft failure, and patient survival. A liver biopsy performed at 1 year posttransplant can help identify those patients more likely to develop progressive disease and may allow better targeting of antiviral therapy.
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PMID:One-year protocol liver biopsy can stratify fibrosis progression in liver transplant recipients with recurrent hepatitis C infection. 1537 4


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