Unusual presentations of enlarged parathyroid cysts: two case reports.

INTRODUCTION: Parathyroid cysts are infrequently encountered and have a variable presentation pattern depending on their size, location and secreting character. PATIENTS AND METHODS: We report two cases of parathyroid cysts characterized by their uncommon clinical presentation. RESULTS: In the first case the patient presented with a large cervical cystic mass without hypercalcemia, while in the second case, the patient experienced a hypercalcemic crisis associated with acute renal failure. The variable pattern of clinical manifestations is discussed. CONCLUSION: Parathyroid cysts are a rare entity. Surgical resection is the key to therapy when hyperparathyroidism or local compression are identified.

Pharmacogenetic-based strategy using de novo tacrolimus once daily after kidney transplantation: prospective pilot study.

AIM: The once daily tacrolimus formulation (Tac-OD) has been associated with better patient adherence and low variability in exposure. Patients carrying the CYP3A5*1 allele show accelerated clearance of Tac. Authors prospectively evaluate a simplified strategy for Tac-OD administration. PATIENTS & METHODS: After grafting, 151 patients were divided into four groups and received a daily dose calculated according to CYP3A5 genotypes and unchanged for the first 3 days: CYP3A5*3/*3: 0.20 mg/kg/day, CYP3A5*3/*3: 0.25 mg/kg/day, CYP3A5*1/*3: 0.30 mg/kg/day and CYP3A5*1/*1: 0.35 mg/kg/day. The dose was adaptated on day 4 and remained unchanged a further three days and so on. RESULTS: On day 3, median Cmin fell within the therapeutic range in all study groups. CYP3A5 expressors require significantly higher Tac-OD throughout the follow-up period to achieve a comparable Cmin. CONCLUSION: This simplified strategy does not hamper treatment efficacy.

Is plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) determination in donors and recipients predictive of renal function after kidney transplantation?

OBJECTIVES: Delayed graft function (DGF) is still a major issue in kidney transplantation. Plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) were evaluated in a population of kidney donors and recipients to investigate their performance to predict early renal function. DESIGN AND METHODS: Plasma (pNGAL) and urine (uNGAL) samples were obtained from donors before organ procurement, and from recipients before transplantation, and then 6, 24 and 48h after the procedure. Kidney transplantations were performed from both living donors (LDs, n=17) and deceased donors (DDs, n=80). Recovery of renal function was evaluated as the time to reach serum creatinine <2mg/l or glomerular filtration rate (GFR)>40mL/min. Logistic regression was used to assess the ability of different variables to predict the occurrence of DGF. RESULTS: Plasma NGAL levels were significantly lower in LDs than in DDs. No episodes of DGF were recorded among LD kidney recipients, but DGF was observed in 25% of patients in the DD group. There was no correlation between donor pNGAL and uNGAL values and the occurrence of post-transplant DGF. Recipient pNGAL performed better than uNGAL in terms of predicting DGF occurrence. Donor pNGAL and uNGAL values did not influence the time needed to reach serum creatinine levels of <2mg/dl after transplantation. When time to reach eGFR of >40mL/min is considered, only donor uNGAL seems to be a predictor of graft function recovery. However, recipient pNGAL values obtained 24 and 48h after transplantation, but not uNGAL values, were found to be a significant predictor of graft function recovery. CONCLUSIONS: Plasma NGAL level determination in recipients, but not in donors, proved to be a reliable predictor of DGF occurrence and renal function restoration, but too long for an interval to be able to compete with biomarkers currently used in clinical practice.

Impact of CYP3A4*22 allele on tacrolimus pharmacokinetics in early period after renal transplantation: toward updated genotype-based dosage guidelines.

BACKGROUND: Tacrolimus (Tac) metabolism is mainly mediated by the cytochrome P450 3A (CYP3A) subfamily. Recently, it has been reported that kidney transplant recipients carrying the CYP3A4*22 decrease-of-function allele require lower Tac doses and are more at risk of Tac overexposure than CYP3A4*1/*1 patients. This effect was shown to be independent of the CYP3A5*3 allelic status. However, the pharmacokinetic (PK) parameters assessed in previous studies were limited on single time point whole blood trough concentrations (C0) during routine follow-up of the patient after transplantation. METHODS: Our study investigates the impact of the CYP3A4*22 allele on Tac PK [C0, area under the time vs concentration curve (AUC0-12h), apparent clearance (Cl/F), Cmax, and dose requirement], time to achieve target C0, and creatinine clearance (CrCl) in 96 kidney transplant recipients considering the 2 first weeks after the graft. All patients were genotyped for both the CYP3A4*22 and the CYP3A5*3 polymorphisms. RESULTS: CYP3A4*22 carriers had higher Tac C0 during the first week with significant longer exposures to C0 > 15 ng/mL. These patients showed reduced Tac Cl/F but higher dose-adjusted AUC0-12h and Cmax and were at increased risk of C0 > 20 ng/mL. These effects were independent from CYP3A5*3 genotype: clustering patients according to both CYP3A4*22 and CYP3A5*3 allelic status did increase the predictive value of the genotype to explain interindividual differences in Tac PK. During the second week after transplantation, CrCl was on average 9.5 mL/min higher for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (P = 0.007), suggesting that Tac overexposure in CYP3A4*22 carriers might provide a renal function benefit. CONCLUSIONS: Our study confirms the decreased CYP3A4 activity toward Tac for CYP3A4*22 carriers early after transplantation and provides evidence for refining genotype-based dosage by adding the CYP3A4*22 genotype information to the CYP3A5*3 allelic status.

Renal allograft implantation on prosthetic vascular grafts: short- and long-term results.

BACKGROUND: Arterial anastomosis in transplant patients with severe aortic and iliac atheromatosis is technically challenging and may jeopardize the success of the transplantation procedure. The aim of this retrospective study was to report short- and long-term results of a consecutive series of kidney transplant patients in whom the renal artery was implanted on a prosthetic vascular graft. MATERIALS AND METHODS: Medical charts and outpatient clinical records of patients who had undergone renal artery implantation on a prosthetic graft were reviewed. Data on patient characteristics, indications for transplantation, prior vascular procedures, surgical technique, and postoperative and long-term outcome were collected. RESULTS: The renal artery was implanted on a prosthetic graft in the course of 27 kidney transplantation procedures. Patients were divided into three groups according to the timing of the vascular intervention in relation to the transplantation. In group A (n = 22), the vascular prosthesis was implanted before kidney transplantation, in group B (n = 2), prosthetic iliac artery replacement and kidney transplantation were performed simultaneously, while in group C (n = 3), the vascular prosthesis was implanted after kidney transplantation. After a median follow-up of 50.5 months, one case of early arterial thrombosis was observed (3.7 %). Infectious complications occurred in two patients (7.4 %) related to mycotic pseudoaneurysms. One hematoma and one evisceration were also encountered, but no late arterial thrombosis nor stenosis were noted. Mean creatinine levels at 1 and 5 years of follow-up were 1.32 ± 0.36 and 1.27 ± 0.56 mg/dl, respectively. Five-year patient and graft survival rates were 85.2 and 74 %, respectively. CONCLUSIONS: Grafting of the renal artery to a vascular prosthesis is feasible and yields good results, despite the technical difficulties involved. We stress the importance of good teamwork.

Donor age and ABCB1 1199G>A genetic polymorphism are independent factors affecting long-term renal function after kidney transplantation.

BACKGROUND: In renal tubular cells, cytochrome P4503A enzyme and adenosine triphosphate-binding cassette transporter activities result in intracellular drug or metabolite exposure variability, depending on genetic polymorphisms. Our aim was to establish whether long-term renal function is affected by genetic polymorphisms in biotransformation enzymes and drug transporters of the donor after kidney transplantation. MATERIALS AND METHODS: The study was conducted in a selected cohort of 97 kidney recipients. Genotyping of donors was performed on renal biopsy samples obtained before transplantation. Serum creatinine levels and Cockcroft-Gault estimated glomerular filtration rate were considered 1 y after transplantation and at the last follow-up. RESULTS: Long-term function was significantly better in recipients of an organ from donors carrying the ABCB1 1199A mutated allele (median and range creatinine values were 1.1 mg/dL [0.8-1.5mg/dL] in case of at least one ABCB1 1199A allele versus 1.5 mg/dL [0.7-3.7 mg/dL] for homozygous carriers of wild-type allele, P < 0.01). ABCB1 1199G>A polymorphism and donor age had an independent impact on both serum creatinine and estimated glomerular filtration rate. Unlike donor age, the mutated ABCB1 1199A allele was found to have a protective effect on renal function. CONCLUSIONS: Donor age and ABCB1 1199G>A polymorphism affect long-term renal function after transplantation. Analysis of genetic factors offers a promising approach to calcineurin inhibitor toxicity risk assessment.

Kidney donation after circulatory death in a country with a high number of brain dead donors: 10-year experience in Belgium.

Worldwide shortage of standard brain dead donors (DBD) has revived the use of kidneys donated after circulatory death (DCD). We reviewed the Belgian DCD kidney transplant (KT) experience since its reintroduction in 2000. Risk factors for delayed graft function (DGF) were identified using multivariate analysis. Five-year patient/graft survival was assessed using Kaplan-Meier curves. The evolution of the kidney donor type and the impact of DCDs on the total KT activity in Belgium were compared with the Netherlands. Between 2000 and 2009, 287 DCD KT were performed. Primary nonfunction occurred in 1% and DGF in 31%. Five-year patient and death-censored graft survival were 93% and 95%, respectively. In multivariate analysis, cold storage (versus machine perfusion), cold ischemic time, and histidine-tryptophan-ketoglutarate solution were independent risk factors for the development of DGF. Despite an increased number of DCD donations and transplantations, the total number of deceased KT did not increase significantly. This could suggest a shift from DBDs to DCDs. To increase KT activity, Belgium should further expand controlled DCD programs while simultaneously improve the identification of all potential DBDs and avoid their referral for donation as DCDs before brain death occurs. Furthermore, living donation remains underused.

Randomized clinical trial on Harmonic Focus shears versus clamp-and-tie technique for total thyroidectomy.

BACKGROUND: The Harmonic Focus is the last ultrasonic device designed for thyroid surgery. The aim is to assess its efficacy and safety compared with traditional dissection in a prospective randomized trial of total thyroidectomy procedures. METHODS: Total thyroidectomy was performed in 34 patients using the Harmonic Focus, and in 34 patients using the clamp-and-tie technique. RESULTS: In the Harmonic Focus group, relative reductions of 29% and 46% were observed in surgical time and blood loss, respectively. The number of intraoperative instrument exchanges also decreased by 70%, and use of specific materials required to achieve hemostasis decreased significantly. Safety was found to be similar in both patient groups. CONCLUSIONS: Our study showed beneficial effects of Harmonic Focus use in thyroid surgery. Further studies therefore are needed to evaluate cost in the light of savings made in surgical time, materials needed for hemostasis, and human resources.

CYP3A5 and ABCB1 polymorphisms influence tacrolimus concentrations in peripheral blood mononuclear cells after renal transplantation.

AIMS: This prospective study investigated the effect of genetic polymorphisms in a biotransformation enzyme (CYP3A5) and a transporter protein (ABCB1) on tacrolimus (Tac) whole blood concentrations in renal transplantation, and more specifically on peripheral blood mononuclear cell (PBMC) drug concentrations, after renal transplantation. MATERIALS & METHODS: A total of 96 renal transplant recipients were genotyped for the exon 11 (1199G>A), 21 (3435C>T) and 26 (2677G>T/A) polymorphisms in the ABCB1 gene and for the intron 3 polymorphism in the CYP3A5 gene. Tac blood and PBMC concentrations were determined at day 7 after transplantation and at steady state, and then compared with recipient genotypes. RESULTS & CONCLUSION: The ABCB1 1199G>A, 3435C>T and 2677G>T/A SNPs, appeared to reduce the activity of P-glycoprotein towards Tac, increasing Tac PBMC concentrations. The impact of ABCB1 genetic polymorphisms on Tac blood concentrations was negligible. As increased Tac intracellular concentrations might in turn enhance immunosuppressive status and prevention or rejection, ABCB1 recipient genotyping might be useful to better individualize the Tac immunosuppressive therapy in renal transplantation.

Biotransformation enzymes and drug transporters pharmacogenetics in relation to immunosuppressive drugs: impact on pharmacokinetics and clinical outcome.

Immunosuppressive drugs commonly used after organ transplantation to prevent acute rejection including tacrolimus, cyclosporine, sirolimus, and mycophenolic acid are characterized by a narrow therapeutic index and broad interindividual variability in their pharmacokinetics. Adequate immunosuppression aims to reach an optimal benefit-risk ratio. Therapeutic drug monitoring represents a crucial step in routine practice to maintain blood concentrations within the target window, because the bioavailability of these drugs depends on their absorption, distribution, biotransformation, and elimination. Single nucleotide polymorphisms (SNPs) in genes encoding biotransformation enzymes (CYP3A) and drug transporters (ABCB1) have opened up a promising way for the selection of individual dosages. The relationship of these SNPs with immunosuppressive drug pharmacokinetics was extensively studied after kidney, liver, heart, and lung transplantations. Patient susceptibility to nephrotoxicity in the long term was also reported in relation to some SNPs, which could allow effective assessment of individual risk and selection of treatment according to patient parameters. Further studies are needed to provide evidence that a genetic analysis combined with therapeutic drug monitoring has the potential to optimize drug use after transplantation.

Comparison of the effects of aprotinin and tranexamic acid on blood loss and red blood cell transfusion requirements during the late stages of liver transplantation.

BACKGROUND: During liver transplantation (LT), profound activation of the fibrinolytic system can contribute significantly to perioperative bleeding. Prophylactic administration of antifibrinolytic agents has been shown to reduce blood loss and the need for allogeneic transfusion in these conditions. STUDY DESIGN AND METHODS: This prospective randomized trial included 51 cirrhotic patients undergoing LT. Patients were randomly assigned to receive either 280 mg of aprotinin (AP) followed by 70 mg per hour or 40 mg per kg tranexamic acid (TA) followed by 40 mg per kg per hour, administered from the end of the anhepatic phase until 2 hours after reperfusion of the graft, and the effects on blood loss and red blood cell (RBC) transfusion requirements were compared. Transfusion policy was standardized in all patients. In addition, the biological effects of the two drugs, as assessed by coagulation and fibrinolytic markers obtained during surgery, were evaluated in a subgroup of patients from each treatment group and compared with an historical control group that did not receive antifibrinolytic drugs. RESULTS: There was no significant difference between the two groups in perioperative blood losses (AP, 6200 [4620-8735] mL; TA, 5945 [4495-8527] mL; median [range]) or in RBC transfusions requirements (AP, 9 [6.75-15.25] units; TA, 10 [6.5-13.5] units). Inhibition of fibrinolysis was observed with both drugs compared with the control group. Coagulation appeared to be activated more with AP, however, whereas fibrinolysis was inhibited more by TA. CONCLUSION: Blood losses and RBC transfusion requirements were comparable regardless of the drug administered. TA may be as valuable as AP for controlling fibrinolysis in LT.

Pediatric en bloc dual kidney-pancreas transplantation into an adult recipient: a simplified technique. Benefits of the en bloc kidney-pancreas transplantation technique in pediatric donors.

The lower age limit for pancreas donors is not well defined. Fear of inadequate islet beta-cell mass and of technical complications has hampered the use of pediatric donors. A surgical technique of 'en bloc' kidney-pancreas is described. Both kidneys and pancreas were removed en bloc from a 13-kg, 31-month-old child. During bench preparation, one anastomosis was performed between the portal vein and the inferior vena cava. The proximal end of the aorta was closed. The bloc was transplanted into a 36-year-old type I diabetic patient intraperitoneally in the right iliac fossa. The kidneys functioned immediately. Pancreatic graft function resumed after POD 15 but insulin therapy was maintained until POD 112. Currently, the patient retains excellent kidney and pancreas graft functions. Very young donors can be accepted as pancreas donors for adult recipients, although slow recovery of pancreatic function can be expected. Use of the en bloc technique is well suited for very small children, as it prevents potential vascular complications.

Infusion of donor-derived hematopoietic stem cells in organ transplantation: clinical data.

Many strategies for tolerance induction have been developed, because this is the major goal of clinical transplantation. One of the most effective and best-studied approaches has been based on the injection of hematopoietic cells derived from the donor bone marrow, to establish a state of microchimerism in the recipient. A subset of hematopoietic stem cells might be responsible for the tolerogenic properties. These CD34+ bone marrow stem cells can be isolated and safely injected into kidney transplant recipients. In the authors' clinical trial, no adverse effects were observed, and the infusion of donor CD34+ cells was well tolerated.

Reduction of left ventricular diameter and mass after surgical arteriovenous fistula closure in renal transplant recipients.

BACKGROUND: Left ventricular hypertrophy and dilatation is a frequent finding in kidney transplant recipients, which may be favored by the persistent patency of arteriovenous fistula. The purpose of the current study was to prospectively investigate whether surgical closure of the fistula allows reduction of abnormalities of left ventricular morphology in stable renal transplant patients. Furthermore, we studied the ability of preoperative echocardiographic and noninvasive hemodynamic measurements, including the effects of a temporary occlusion of the fistula, to predict postoperative left ventricular diameter and mass reduction. METHODS: Seventeen kidney transplant recipients referred for surgical arteriovenous fistula closure were prospectively studied. Standard echocardiographic parameters, heart rate, and blood pressure were assessed preoperatively at baseline and during an acute pneumatic fistula occlusion. These measurements were repeated 3 to 10 weeks after surgical closure. Six kidney transplant recipients with patent arteriovenous fistulas referred for routine echocardiographic follow-up served as a control group. RESULTS: Surgical fistula closure decreased left ventricular end-diastolic diameter and mass indexes (29.9+/-2.4 to 27.4+/-2.1 mm/m2, P<0.001, and 141+/-37 to 132+/-39 g/m2, P<0.05, respectively), whereas no changes were seen in controls after a similar delay. Postoperative left ventricular end-diastolic diameter and mass reductions correlated best with the increases in total peripheral resistance (r=0.85, P<0.0001) and mean arterial blood pressure (r=0.64, P=0.006) during pneumatic occlusion, respectively. CONCLUSIONS: Surgical closure of arteriovenous fistula reduces left ventricular diameter and mass in kidney transplant recipients. Increases in blood pressure and total peripheral resistance induced by temporary fistula occlusion are the best predictors of these morphological changes.

Caliceal fistula in kidney transplantation. The role of magnetic resonance imaging.

Caliceal fistula is a rare complication of renal transplantation, which often raises some diagnostic problems. We report the case of a patient in which this complication occurred and in whom the diagnosis could be clearly demonstrated by using magnetic resonance imaging (MRI). On the T1-weighted images, a perirenal collection was depicted by a low signal intensity. On T2-weighted images, the collection appeared with a high signal intensity, and a linear hyperintensity was observed on the internal graft's labium at the level of the inferior pole corresponding to a caliceal fistula arising from the lower pole of the graft. In this setting, the use of MRI is compared with the other diagnostic techniques (sonography, CT scan, nephrogram, scintigraphy). MRI constitutes a progress in imaging of the renal graft by its high definition and the lack of nephrotoxicity. Its place remains, however, to be more precisely defined in the evaluation of a renal graft's complications.