Plerixafor on-demand combined with chemotherapy and granulocyte colony-stimulating factor: significant improvement in peripheral blood stem cells mobilization and harvest with no increase in costs.

To date, no prospective study on Plerixafor 'on-demand' in combination with chemotherapy and granulocyte colony-stimulating factor (G-CSF) has been reported. We present an interim analysis of the first prospective study in which Plerixafor was administered on-demand in patients affected by multiple myeloma and lymphoma who received high dose cyclophosphamide or DHAP (dexamethasone, cytarabine, cisplatin) plus G-CSF to mobilize peripheral blood stem cells (PBSC). One hundred and two patients were evaluable for response. A cohort of 240 patients receiving the same mobilizing chemotherapy was retrospectively studied. Failure to mobilize CD34(+) cells in peripheral blood was reduced by 'on-demand' strategy compared to conventional mobilization; from 13·0 to 3·0% (P = 0·004). Failure to harvest CD34(+) cells 2 × 10(6) /kg decreased from 20·9 to 4·0% (P = 0·0001). The on-demand Plerixafor strategy also resulted in a lower rate of mobilization failure (P = 0·03) and harvest failure (P = 0·0008) when compared to a 'bias-adjusted set of controls'. Evaluation of economic costs of the two strategies showed that the overall cost of the two treatments were comparable when salvage mobilizations were taken into account. When in combination with cyclophosphamide or DHAP plus G-CSF, the 'on-demand' use of Plerixafor showed, in comparison to conventionally treated patients, a significant improvement in mobilization of PBSC with no increase in overall cost.

Successful medical treatment of EBV smooth muscle tumor in a renal transplant recipient.

EBV is associated with various malignancies in patients with acquired or induced immune impairment. EBV-SMT is very uncommon in immunocompromised patients, and a kidney localization has been described only anecdotally. We report the case of a 17-yr-old kidney transplant recipient diagnosed as having an EBV-SMT inside the renal graft, which was successfully managed by minimizing isolated immunosuppression.

[Role of C-peptide in the pathogenesis of diabetic nephropathy]. / Ruolo del C-peptide nella patogenesi della nefropatia diabetica.

Insulin and C-peptide are secreted by pancreatic beta cells in equimolar amounts. Although C-peptide has long been believed to have no biological function, in recent years this molecule has been recognized as an independent hormone with a specific G-protein-coupled receptor. Recent evidence suggests that C-peptide may also have a specific nephroprotective effect, particularly in cases of diabetic nephropathy. In animal models of diabetes this beneficial effect has been repeatedly confirmed. Contradictory results have been obtained in humans: on the one hand it was shown that patients with diabetic nephropathy have lower plasma levels of C-peptide than patients with diabetes of similar duration and normal renal function; on the other hand it is also evident that patients affected by type 2 diabetes develop nephropathy even in the presence of high plasma levels of C-peptide, suggesting that in humans C-peptide is likely to have multifaceted activity. This review describes the different arguments supporting or contrasting the notion of C-peptide as a potential new therapy for diabetic nephropathy. It is possible that only a well performed, large-scale clinical study with careful evaluation of the positive and negative effects of C-peptide will finally clarify whether C-peptide reintegration in patients with type 1 diabetes is able to prevent the development and/or control the progression of diabetic nephropathy.

[Retroperitoneal renal hemorrhage: experience of our dialysis center].

The aging of the uremic population, the increasingly common use of anticoagulants, antiplatelet agents e heparin, during hemodialysis, can expose our patients to a greatest risk of bleeding. Spontaneous retroperitoneal hematomas are a fairly rare and potentially fatal condition. We describe 5 clinical cases of retroperitoneal hemorrhage that we observed during 10 years in our department, focusing on modalities of symptom onset, clinical-laboratory picture and treatment modalities.

What every doctor should know about drug safety in patients with chronic kidney disease.

Drug safety is a very relevant issue when dealing with patients with chronic kidney disease (CKD) who need vascular access procedures and interventions. Drug dosage adjustments are needed for patients with acute or chronic kidney disease. In CKD patients, the estimated glomerular filtration rate is used to guide dose adjustments. Determining the influence of renal replacement therapies on drug dosage adjustment is also very important. Safety issues for the following drugs used for situations related to vascular access are reported: anticoagulants and antiplatelet agents, antibiotics, antimicrobials for catheter lock therapy, thrombolytics, local anesthetics, and painkillers. General principles of the interactions of drugs in CKD are also reported.

Salvage therapy of multiple myeloma: the new generation drugs.

During the past decade, overall results of treatment of multiple myeloma (MM) have been improved and survival curves are now significantly better with respect to those obtained with historical treatment. These improvements are linked to a deeper knowledge of the biology of disease and to the introduction in clinical practice of drugs with different mechanism of action such as proteasome inhibitors and immunomodulatory drugs (IMiDs). However, MM remains in most cases an incurable disease. For patients who relapse after treatment with novel agents, the prognosis is dismal and new drugs and therapeutic strategies are required for continued disease control. In this review, we summarize new insights in salvage therapy for relapsed/refractory MM as emerging from recent clinical trials exploring the activity of bendamustine, new generation proteasome inhibitors, novel IMiDs, monoclonal antibodies, and drugs interfering with growth pathways.

Rosuvastatin-induced acute interstitial nephritis.

We report a case of acute interstitial nephritis (AIN), most likely induced by rosuvastatin, in an 83-year-old male patient. The patient underwent angioplasty of the left internal carotid artery, after which he began a regimen of rosuvastatin (20 mg/day). After 3 weeks the patient was admitted to our unit for acute renal failure with mild proteinuria with negligible urinary sediment. A left kidney biopsy showed dense interstitial infiltrates, mainly composed of lymphocytes with evident tubulitis. Rosuvastatin withdrawal plus prednisolone (1 mg/kg/day) treatment, which was slowly tapered over a period of 4 weeks, allowed for a complete recovery of renal function. To our knowledge, this is the first case report of rosuvastatin-induced AIN. Acute renal failure is associated with a clear increase in morbidity, length of hospital stay and mortality. Moreover, since statins are among the most widely prescribed drugs in Western countries, we think that the risk of AIN should be taken into account as a possible side effect of rosuvastatin.

Vitamin d receptor activators and clinical outcomes in chronic kidney disease.

Vitamin D deficiency appears to be an underestimated risk factor for cardiovascular disease in patients with chronic kidney disease. Evidence from both basic science and clinical studies supports the possible protective role of vitamin D beyond its effect on mineral metabolism. Toxicity of pharmacologic doses of active vitamin D metabolites, in particular calcitriol, is mainly due to the possibility of positive calcium and phosphorus balance. Therefore, vitamin D analogs have been developed, which suppress PTH secretion and synthesis with reduced calcemic and phosphatemic effects. Observational studies suggest that in hemodialysis patients the use of a vitamin D receptor (VDR) activator, such as calcitriol, doxercalciferol, paricalcitol, or alfacalcidol, is associated with a reduced mortality when compared with nonusers of any VDR activator. In this article the existing literature on the topic is reviewed, although a more robust answer to the question of whether or not VDR activators have beneficial effects in hemodialysis patients will hopefully come from a randomized controlled trial.

Central venous catheters: legal issues.

In dialysis patients, both central venous catheter (CVC) insertion and CVC use during the dialysis procedure pose important legal issues, because of potentially severe, even fatal, complications. The first issue is the decision of the kind of vascular access that should be proposed to patients: an arteriovenous (AV) fistula, a graft, or a CVC. The second issue, when choosing the CVC option, is the choice of CVC: nontunneled versus tunneled. Leaving a temporary nontunneled CVC for a prolonged time increases the risk of complications and could raise a liability issue. Even when choosing a long-term tunneled CVC, nephrologists should systematically explain its potential harms, presenting them as "unsafe for long-term use" unless there is a clear contraindication to an AV native or prosthetic access. Another critical issue is the preparation of a complete, informative, and easy-to-understand consent form. The CVC insertion procedure has many aspects of legal interest, including the choice of CVC, the use of ECG monitoring, the use of ultrasound guidance for cannulation, and the use of fluoroscopy for checking the position of the metal guidewire during the procedure as well as the CVC tip before the end of the procedure. Use of insertion devices and techniques that can prevent complications should obviously be encouraged. Complications of CVC use are mainly thrombosis and infection. These are theoretically expected as pure complications (and not as malpractice effects), but legal issues might relate to inappropriate catheter care (in both the inpatient and outpatient settings) rather than to the event per se. Thus, in the individual case it is indeed very difficult to establish malpractice and liability with a catheter-related infection or thrombosis. In conclusion, we cannot avoid complications completely when using CVCs, but reducing them to a minimum and adopting safe approaches to their insertion and use will reduce legal liability.

Subclinical impairment of coronary flow velocity reserve assessed by transthoracic echocardiography in young renal transplant recipients.

BACKGROUND: In renal transplant recipients (RTR) an increased risk to develop cardiovascular injury is present. Transthoracic Doppler echocardiographic assessment of coronary flow velocity reserve (CFVR), a sensitive and minimally invasive technique, was recently employed to detect both macrovascular and microvascular coronary artery disease (CAD) in different clinical settings. The prevalence of coronary involvement in young adult RTR is still unknown. The aim of the study was to investigate the presence of early cardiovascular damage in asymptomatic young adult RTR. METHODS: Transthoracic Doppler echocardiographic-derived CFVR and common carotid intima-media thickness (IMT) were assessed in 25 asymptomatic young adult RTR (mean age 25.7+/-7.0 years; range 17.3-43.9) without CAD and 25 healthy controls. RESULTS: CFVR was lower in young adult RTR compared to controls (2.8+/-0.6 vs. 3.5+/-0.8; P<0.001), meanwhile left ventricular wall motion and common carotid IMT were comparable in both groups. We found a negative correlation between CFVR and age (r=-0.50; P=0.018) and months on dialysis (r=-0.54; P<0.01). CONCLUSIONS: Young adult RTR showed a reduced CFVR reflecting an impaired coronary microcirculation, which is significantly related to the age and duration of dialysis; coronary microvascular damage is detectable in the absence of changes in common carotid IMT. Non-invasive evaluation of CFVR by transthoracic stress echocardiography could be a reliable method for identification of early coronary microvascular involvement in young adult RTR.

The effect of CYP3A5 polymorphisms on the pharmacokinetics of tacrolimus in adolescent kidney transplant recipients.

BACKGROUND: CYP3A5 gene polymorphism has been shown to influence tacrolimus (TAC) blood concentration and dose requirement in adult kidney transplant patients. The aim was to analyze retrospectively the modification induced by CYP3A5 gene polymorphism on TAC's pharmacokinetic parameters obtained from 26 adolescents receiving TAC as their main immunosuppressive drug. MATERIAL/METHODS: The adolescent kidney transplant patients were genotyped for CYP3A5*3 and grouped accordingly. TAC dose, blood levels, and dose-normalized TAC blood concentration and volume of distribution obtained at different post-transplant periods during the first post-transplant year were correlated with the corresponding genotype. RESULTS: During the first three months post-transplant, heterozygotes (CYP3A5*1/*3) displayed a lower TAC blood concentration than homozygotes (CYP3A5*3/*3) (at 1 month: 7.8+/-2.1 vs. 13.4+/-6 ng/ml, p=0.007) despite a therapeutic monitoring strategy. Between 3-12 months post-transplant, TAC blood concentration was comparable between the two groups, but a two-fold increase in the daily drug dose was necessary for the heterozygotes (at 6 months: 0.23+/-0.1 vs. 0.13+/-0.06 mg/kg, p=0.04). The dose-normalized TAC concentration [(ng/ml)/(mg/kg)] was significantly lower in patients displaying the CYP3A5*1/*3 polymorphism (at 2 weeks: 33+/-2.16 vs. 71.1+/-37.8, p=0.01; 6 months: 35.4+/-12.9 vs. 85.2+/-58.9, p=0.01). At the same time, the volume of distribution of the drug in the latter group was distinctly increased for the entire post-transplant year (at 6 months: 1.79+/-0.42 vs. 0.73+/-0.5 l/kg, p=0.001). CONCLUSIONS: The great influence of CYP3A5 on the pharmacokinetics and pharmacodynamics of TAC in young transplant recipients suggests the need for pre-transplant screening of this polymorphism to improve TAC therapy.

Influence of the CYP3A5 genotype on tacrolimus pharmacokinetics and pharmacodynamics in young kidney transplant recipients.

CYP3A enzyme plays a pivotal role in TAC metabolism. The aim of this study was to analyze retrospectively the influence of CYP3A5 gene polymorphism on TAC pharmacokinetics and pharmacodynamics in 30 teenage kidney transplant recipients. TAC dose, trough blood levels, apparent volume of distribution, as well as blood pressure and antihypertensive therapy obtained at different post-transplant periods, were correlated with the corresponding genotype. Despite a therapeutic monitoring strategy, heterozygotes (CYP3A5*1/*3) displayed a lower TAC blood concentration compared with homozygotes (CYP3A5*3/*3). Therefore, a two-fold increase of the daily TAC dose was required in the heterozygotes to reach the desired therapeutic target level. A significant group by time interaction effect was present for both variables (repeated measures ANOVA: p = 0.002) meaning a significant different pharmacokinetic response in these two cohorts. Mean blood pressure was also elevated in CYP3A5*1/*3 recipients despite similar antihypertensive treatment. This was parallel with an elevated apparent volume of distribution of TAC in this group. Thus, the allele-effect was correlated with one of the most common TAC side-effects suggesting a possible influence of CYP3A5 polymorphism on TAC pharmacodynamics. The authors concluded that a pre-emptive CYP3A5 pharmacogenetic screening could contribute to better individualization of TAC therapy.

Reduced coronary flow reserve in young adults with renal transplant.

BACKGROUND: Some degree of cardiovascular disease should be suspected in young adults who have been paediatric renal transplant recipients also if no systematic data collection is routinely performed in clinical setting. The aim of our work was to evaluate the degree of cardiovascular damage in these young patients, using a minimally invasive technique. We then evaluated coronary flow reserve (CFR) and carotid intima-media thickness (IMT) in 25 patients (13 males, median age 23.7 years). METHODS: Coronary flow velocity on the left anterior descending coronary artery was assessed by transthoracic echocardiography, before and after dipyridamole, after standard echocardiography. CFR was compared with that of a small control group (n = 16; median age 25 yrs). RESULTS: In this relatively young sample, mean CFR was 2.8 +/- 0.6 (median 2.75), and half of the patients had reduced coronary reserve (P = 0.01). Mean IMT (0.48 +/- 0.08 mm) was only slightly, though significantly larger compared with the reference standard (P < 0.05) but was significantly thinner in normotensive than in hypertensive patients (0.42 +/- 0.06 vs 0.49 +/- 0.05 mm, P < 0.05). The time on dialysis prior to transplantation, hypertension and age at the time of CFR evaluation affect CFR. IMT did not correlate with CFR. CONCLUSIONS: CFR and IMT abnormalities are common in young transplant recipients, in spite of the fact that our paediatric population has much less of the atherosclerotic 'legacy' common to adult patients.