Luisa Berardinelli

Long‐term safety and feasibility of arteriovenous fistulae as vascular accesses in children with haemophilia: a prospective study

Summary. Infectious and thrombotic complications limit the long‐term use of subcutaneous ports as venous accesses for children with haemophilia. This study has evaluated for the first time the safety and feasibility of internal arteriovenous fistulae (AVF) as alternative accesses. During the 3‐year study period, 27 severe haemophiliacs, 14 with factor VIII inhibitors (52%), underwent the creation of 31 proximal AVF in the forearm. Mild forearm haematomas were observed after five procedures (16%) in five patients who had or developed inhibitors after surgery. Inadequate AVF maturation was observed after five of 31 procedures (16%) in four children. AVF were first accessed after a median of 42 d and regularly used at home by 26 patients (96%) for a median follow‐up period of 29 months. Thrombosis of a venous branch occurred in one AVF (3%) after 9 months of uncomplicated use in a child with inhibitor who spontaneously recovered from the symptoms and still used AVF for nine additional months. Mild symptoms, referable to distal ischaemia, were transiently reported by two children (7%) who needed no remedial intervention. This study demonstrates that the use of AVF in haemophiliacs enabled long‐term treatment at home in all patients but one.

Improved treatment feasibility in children with hemophilia using arteriovenous fistulae: the results after seven years of follow-up

Whilst the benefits of prophylactic replacement therapy for children with hemophilia and of immune tolerance for those with inhibitors are both generally accepted, venous access can be a limiting problem in their delivery. In this paper, Mancuso and coworkers report on their extensive experience using arterio-venous fistulae to deal with this problem and suggest they could be more widely adopted. Background An easy and stable venous access is essential in hemophilic children who receive regular prophylaxis or immune tolerance induction treatment. Central venous access devices improve treatment feasibility, but their use is complicated by infection and/or thrombosis. Arteriovenous fistula (AVF) has been evaluated as an alternative to central venous access devices in hemophilic children since 1999. Design and Methods This study provides results obtained in a large series after seven years of follow-up. Results From 1999 to 2008, 43 procedures were performed in 38 children (median age: 2.7 years). Thirty-five AVFs (81%) achieved maturation after a median of 58 days and were used for a median of five years (range: 0.4–8.5). A brachial artery caliber larger than 1.2 mm was associated with successful maturation (p<0.05). Complications with some impact on arteriovenous fistula use or duration were observed in 14/43 procedures (32%) and in 13/38 children (34%). Age at arteriovenous fistula creation was younger in children who lost arteriovenous fistula patency (p<0.05) and aneurysms were more frequent in children who were on daily treatment regimen and thus had a greater cumulative number of arteriovenous fistula accesses (p<0.05). At the end of the follow-up period, 22 AVFs were still in use and 9 had been surgically dismantled. Arteriovenous fistula use allowed long-term prophylaxis (up to 8.5 years) in 11 children and the completion of immune tolerance induction without interruptions in 18 children. Conclusions This study confirms the feasibility of arteriovenous fistula with an acceptable rate of complications and suggests that its use is particularly favorable in children with inhibitors in whom it should be considered as first-choice venous access.

Advantages of cyclosporine as sole immunosuppressive agent in children with transplanted kidneys.

A prospective study of intentional stopping of steroids 6 months after transplantation was done with 29 pediatric renal transplant recipients with a mean age of 10.4±3.4 years. Immunosuppression consisted of cyclosporine and methylprednisolone. We stopped giving MP to 24 children: to twenty after six months, four after 11–20 months. “Crude graft survival” was 97% during a mean follow-up of 36.7±15 months. The rejection rate was 48% during the first 6 months and 29% in the period after stopping MP. At present, 20/24 children (83%) have remained on CsA alone (18 patients) or CsA and azathioprine (2 patients) during a mean follow-up of 30±17 months. CsA nephrotoxicity occurred in 20.6% of patients, gum hypertrophy in 45%, hypertrichosis in 24%, and neurological symptoms in two patients (6.8%). Linear growth significantly improved after stopping MP: mean catch-up growth for prepuberal children 1.38 height standard deviation score (HSDS) and for pubertal children 1.6 HSDS. Bone age did not increase more rapidly than chronologic age. Weight/height index (W/HI) also improved. There was also a significant reduction in the use of antihypertensive drugs. Calculated glomerular filtration rate was decreased, though not significantly, after stopping MP. Thus, when graft survival is good, stopping corticosteroids corrects the major handicap of children with irreversible uremia—the poor linear growth—and improves the W/HI and control of arterial pressure. Longer follow-up periods are necessary to exclude significant worsening of renal function and an increased incidence of chronic rejection after stopping the steroid.

Coming back to dialysis after kidney transplant failure

Advances in immunosuppressive therapy in recent decades have led to excellent renal transplant survival rates at 1 year, but the advantages are lower in the long term. As reported by Meier-Kriesche et al. [1], the actual kidney allograft half-life showed only a marginal improvement over the past decade. Recent data from the United States Renal Data System (USRDS) report an almost invariable 4% annual rate of graft failure among renal transplant recipients [2]. Given the continuing expansion of the transplanted patient pool, this figure translates into a progressive increase in the number of transplanted patients re-entering a dialysis programme [3].

Combined liver-kidney transplantation in glycogen storage disease Ia: A case beyond the guidelines†

Glycogen storage disease type Ia (GSD Ia) is a rare metabolic disorder due to hepatic glucose‐6‐phosphatase deficiency. Although great progress has been made in managing affected patients, severe hypoglycemia, lactic acidosis, hyperlipidemia, hepatic cytolysis, and impaired kidney function are frequent. Liver transplantation is the only radical treatment, for which the main indications are hepatic adenomatosis, hepatocellular carcinoma, or severe hepatic dysfunction. We present the case of a patient with end‐stage renal disease without focal hepatic lesions and with moderate hepatic metabolic control, and we explain how combined liver‐kidney transplantation (LKT) made it possible to correct the metabolic defects responsible for the impaired glucose homeostasis, liberalize the diet, and give birth to a healthy child after an uneventful pregnancy. Patients with end‐stage renal disease that resulted from GSD Ia should be considered for LKT even in the absence of hepatic lesions with the aim of improving their quality of life. Liver Transpl 13:762–764, 2007.

Longitudinal evaluation of mycophenolic acid pharmacokinetics in pediatric kidney transplant recipients. The role of post-transplant clinical and therapeutic variables

Abstract:  This longitudinal study assessed the influence of post‐transplant clinical and therapeutic variables in 50 kidney transplant recipients aged 2–19 yr receiving a triple immunosuppressive regimen consisting of cyclosporine microemulsion (CsA), steroids and MMF (300–400 mg/m2 body surface area twice daily), the full pharmacokinetic profile (10 points) of which was investigated on post‐transplant days 6, 30, 180 and 360. Total plasma MPA was measured by Enzyme Multiplied Immunoassay Technique. CsA therapeutic drug monitoring (TDM) was performed via C2 blood monitoring, while MPA TDM via C0. MPA Cmax, tmax, AUC0‐12 and AUC0‐4 pharmacokinetic profile changed significantly during the first post‐transplant year. C0 was a poor predictor of the total MPA exposure [as measured by the area under the concentration‐time curve AUC)], while a truncated AUC was a good surrogate of the 12‐h profile (r = 0.91; p < 0.001) Graft function and cyclosporine therapy influenced MPA pharmacokinetics, as shown by the univariate and multivariate analyses. We conclude that because after transplantation MPA exposure varied over time, a strict TDM is advisable in the pediatric population.

Living Donor Transplantation of Kidneys with Fibromuscular Dysplasia: Indications, Surgical Techniques and Long Term Results in 11 Cases

The incidence of FMD in potential LDs is observed in a range from 2% to 6.6% with a female predominance [1]; it is the second most common anatomical abnormality after multiple renal arteries. FMD still represents a challenge for any decision to harvest the kidney, particularly from a LD, due to the potential risk to develop a renovascular hypertension and/or FMD either in the remnant kidney after donation [2,3,1,4] or in the recipient’s graft [5-7]. Moreover, the problem may only arise at the operative stage since early forms of FMD give rise to no or mild radiographic evidence. This ‘mild’ radiographic evidence has been described by Indudhara [2] as irregularity of the arterial wall without significant stenosis.

C0 or C2 driven cyclosporine monitoring in long-term pediatric kidney transplant recipients: is there any threat for chronic rejection development?

Abstract:  The clinical management of cyclosporine has evolved greatly during the last decade thanks to the use of pharmacokinetic (PK) studies which confirmed the dose relationship between drug exposure and its biological effects. Therefore, cyclosporine PK monitoring during the early phase of the post‐transplant period became essential to avoid over or underexposure to the drug thus preventing the risk of nephrotoxicity or acute rejection episodes. More recently, a simple PK determination based on cyclosporine blood concentration measured 2 h after the morning dose, has proven to be very effective for monitoring cyclosporine exposure in the early postoperative period. In this paper, the authors present a set of PK profiles obtained from a stable, long‐term pediatric kidney transplant population and correlate these parameters with the risk of chronic rejection development. The study shows how cyclosporine monitoring based on the sole trough level determination misled a correct therapeutic behavior, as revealed by the PK parameters that were constantly below the therapeutic threshold in a small patient cohort who eventually developed chronic rejection. The C2 determination should be considered as the gold standard for cyclosporine monitoring in long‐term pediatric recipients.

Acute Allograft Rejection following Interferon Therapy for Hepatitis C in Recipients who have Returned to Dialysis after Kidney Transplant Failure: Case Study:

Interferon-based therapy remains the gold standard for hepatitis C in patients with chronic kidney disease; however, due to the high rate of IFN-induced rejection after transplant, treatment of HCV-infected kidney transplant recipients is recommended only in particular circumstances. We report the case of a 45-year-old Caucasian female with chronic hepatitis C (genotype 1b) who returned to hemodialysis following the complete functional loss of her kidney transplant. She started combination antiviral therapy with peg-IFN-α2a (135 mcg sc weekly) plus ribavirin (200 mg daily) nine months after the re-initiation of hemodialysis. Antiviral therapy was neither effective nor safe; ribavirin was stopped at week 38 due to hemolytic anemia; on-treatment HCV breakthrough was observed at week 48; and acute rejection occurred after four months of IFN-based therapy. Diagnosis of acute allograft rejection was suspected on the grounds of clinical, radiographic, and laboratory data. Allograft nephrectomy was then performed and histology showed acute-on-chronic rejection. This is an uncommon case of IFN-associated kidney rejection in an allograft recipient who had functional loss of her graft and had returned to hemodialysis. In view of the risk of rejection of renal allograft, and the limited efficacy of IFN-based treatment of hepatitis C, physicians should be aware of effective treatment with oral antiviral agents and avoid the use of IFN in patients on maintenance dialysis with failed renal allograft.